Substituted nucleosides, nucleotides and analogs thereof

ABSTRACT

Disclosed herein are nucleotide analogs, methods of synthesizing nucleotide analogs and methods of treating diseases and/or conditions such as a HCV infection with one or more nucleotide analogs.

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

Any and all applications for which a foreign or domestic priority claimis identified in the Application Data Sheet as filed with the presentapplication, are hereby incorporated by reference under 37 CFR 1.57.

REFERENCE TO SEQUENCE LISTING

The present application is being filed along with a Sequence Listing inelectronic format. The Sequence Listing is provided as a file entitledSEQLISTING_65.TXT, created Feb. 13, 2014, which is 1 Kb in size. Theinformation in the electronic format of the Sequence Listing isincorporated herein by reference in its entirety.

BACKGROUND

Field

The present application relates to the fields of chemistry, biochemistryand medicine. More particularly, disclosed herein are nucleotideanalogs, pharmaceutical compositions that include one or more nucleotideanalogs and methods of synthesizing the same. Also disclosed herein aremethods of treating diseases and/or conditions with a nucleotide analog,alone or in combination therapy with one or more other agents.

Description

Nucleoside analogs are a class of compounds that have been shown toexert antiviral and anticancer activity both in vitro and in vivo, andthus, have been the subject of widespread research for the treatment ofviral infections. Nucleoside analogs are usually therapeuticallyinactive compounds that are converted by host or viral enzymes to theirrespective active anti-metabolites, which, in turn, may inhibitpolymerases involved in viral or cell proliferation. The activationoccurs by a variety of mechanisms, such as the addition of one or morephosphate groups and, or in combination with, other metabolic processes.

SUMMARY

Some embodiments disclosed herein relate to a compound of Formula (I) ora pharmaceutically acceptable salt thereof.

Some embodiments disclosed herein relate to a method of amelioratingand/or treating a hepatitis C viral (HCV) infection that can includeadministering to a subject identified as suffering from the HCVinfection an effective amount of one or more compounds of Formula (I),or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof. Other embodiments describedherein relate to using one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for ameliorating and/or treating a HCV infection. Still otherembodiments described herein relate to one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof, that can be used forameliorating and/or treating a HCV infection.

Some embodiments disclosed herein relate to a method of amelioratingand/or treating a HCV infection that can include contacting a cellinfected with the hepatitis C virus with an effective amount of one ormore compounds described herein, or a pharmaceutically acceptable saltof one or more compounds described herein, or a pharmaceuticalcomposition that includes one or more compounds described herein, or apharmaceutically acceptable salt thereof. Other embodiments describedherein relate to using one or more compounds described herein, or apharmaceutically acceptable salt of one or more compounds describedherein, in the manufacture of a medicament for ameliorating and/ortreating a HCV infection that can include contacting a cell infectedwith the hepatitis C virus with an effective amount of said compound(s).Still other embodiments described herein relate to one or more compoundsdescribed herein, or a pharmaceutically acceptable salt of one or morecompounds described herein, or a pharmaceutical composition thatincludes one or more compounds described herein, or a pharmaceuticallyacceptable salt thereof, that can be used for ameliorating and/ortreating a HCV infection by contacting a cell infected with thehepatitis C virus with an effective amount of said compound(s).

Some embodiments disclosed herein relate to a method of inhibitingreplication of a hepatitis C virus that can include contacting a cellinfected with the hepatitis C virus with an effective amount of one ormore compounds described herein, or a pharmaceutically acceptable saltof one or more compounds described herein, or a pharmaceuticalcomposition that includes one or more compounds described herein, or apharmaceutically acceptable salt thereof. Other embodiments describedherein relate to using one or more compounds described herein, or apharmaceutically acceptable salt of one or more compounds describedherein, in the manufacture of a medicament for inhibiting replication ofa hepatitis C virus that can include contacting a cell infected with thehepatitis C virus with an effective amount of said compound(s). Stillother embodiments described herein relate to one or more compoundsdescribed herein, or a pharmaceutically acceptable salt of one or morecompounds described herein, or a pharmaceutical composition thatincludes one or more compounds described herein, or a pharmaceuticallyacceptable salt thereof, that can be used for inhibiting replication ofa hepatitis C virus by contacting a cell infected with the hepatitis Cvirus with an effective amount of said compound(s).

Some embodiments disclosed herein relate to a method of amelioratingand/or treating a HCV infection that can include administering to asubject identified as suffering from the HCV infection an effectiveamount of a compound described herein or a pharmaceutically acceptablesalt thereof (for example, one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof), or a pharmaceuticalcomposition that includes a compound described herein, or apharmaceutically acceptable salt thereof, in combination with an agentselected from an interferon, ribavirin, a HCV protease inhibitor, a HCVpolymerase inhibitor, a NS5A inhibitor, an other antiviral compound, acompound of Formula (AA), a compound of Formula (BB) and a compound ofFormula (CC), or a pharmaceutically acceptable salt of any of theforegoing. Some embodiments disclosed herein relate to a method ofameliorating and/or treating a HCV infection that can include contactinga cell infected with the HCV infection with an effective amount of acompound described herein or a pharmaceutically acceptable salt thereof(for example, one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof), or a pharmaceuticalcomposition that includes a compound described herein, in combinationwith an agent selected from an interferon, ribavirin, a HCV proteaseinhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, an otherantiviral compound, a compound of Formula (AA), a compound of Formula(BB) and a compound of Formula (CC), or a pharmaceutically acceptablesalt of any of the foregoing. Some embodiments disclosed herein relateto a method of inhibiting replication of a hepatitis C virus that caninclude administering to a subject identified as suffering from a HCVinfection an effective amount of a compound described herein or apharmaceutically acceptable salt thereof (for example, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof), or apharmaceutical composition that includes a compound described herein, ora pharmaceutically acceptable salt thereof, in combination with an agentselected from an interferon, ribavirin, a HCV protease inhibitor, a HCVpolymerase inhibitor, a NS5A inhibitor, another antiviral compound, acompound of Formula (AA), a compound of Formula (BB) and a compound ofFormula (CC), or a pharmaceutically acceptable salt of any of theforegoing. In some embodiments, the agent can be a compound, or apharmaceutically acceptable salt thereof, selected from Compound1001-1016, 2001-2012, 3001-3014, 4001-4012, 5001-5012, 6001-6078,7000-7027 and 8000-8016, or a pharmaceutical composition that includesone or more of the aforementioned compounds, or a pharmaceuticallyacceptable salt of the foregoing. In some embodiments, the method caninclude administering a second agent selected from an interferon,ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5Ainhibitor, an other antiviral compound, a compound of Formula (AA), acompound of Formula (BB) and a compound of Formula (CC), or apharmaceutically acceptable salt of any of the foregoing.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows example HCV protease inhibitors.

FIG. 2 shows example nucleoside HCV polymerase inhibitors.

FIG. 3 shows example non-nucleoside HCV polymerase inhibitors.

FIG. 4 shows example NS5A inhibitors.

FIG. 5 shows example other antivirals.

FIG. 6 shows example compounds of Formula (CC) andalpha-thiotriphosphates thereof, wherein Formula (CC) andalpha-thiotriphosphates thereof are described herein.

FIG. 7 shows example compounds of Formula (AA), wherein Formula (AA) isdescribed herein.

FIG. 8 shows example compounds of Formula (BB), wherein Formula (BB) isdescribed herein.

FIG. 9 shows example compounds of Formula (I), wherein Formula (I) isdescribed herein.

FIG. 10 shows the gels from the assessment of incorporation of severalcompound with a uracil base by the human mitochondrial RNA polymerase.

FIG. 11 shows the gels from the assessment of incorporation of severalcompounds with a guanine base by the human mitochondrial RNA polymerase.

FIGS. 12A-D shows the results of the inhibition of mitochondrial proteinsynthesis assays.

DETAILED DESCRIPTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there are aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise.

As used herein, any “R” group(s) such as, without limitation, R¹, R²,R³, R⁴, R^(5A), R^(5B), R^(6A), R^(6B), R^(6C), R^(6D), R^(6E), R^(6F),R^(6G), R^(6H), R^(7A), R^(7B), R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁷, R¹⁸, R^(A1), R^(A2), R^(A3) and R^(A4) represent substituentsthat can be attached to the indicated atom. An R group may besubstituted or unsubstituted. If two “R” groups are described as being“taken together” the R groups and the atoms they are attached to canform a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. Forexample, without limitation, if R^(a) and R^(b) of an NR^(a)R^(b) groupare indicated to be “taken together,” it means that they are covalentlybonded to one another to form a ring:

In addition, if two “R” groups are described as being “taken together”with the atom(s) to which they are attached to form a ring as analternative, the R groups are not limited to the variables orsubstituents defined previously.

Whenever a group is described as being “optionally substituted” thatgroup may be unsubstituted or substituted with one or more of theindicated substituents. Likewise, when a group is described as being“unsubstituted or substituted” if substituted, the substituent(s) may beselected from one or more the indicated substituents. If no substituentsare indicated, it is meant that the indicated “optionally substituted”or “substituted” group may be substituted with one or more group(s)individually and independently selected from alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano,halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro,silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy,trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, amono-substituted amino group and a di-substituted amino group.

As used herein, “C_(a) to C_(b)” in which “a” and “b” are integers referto the number of carbon atoms in an alkyl, alkenyl or alkynyl group, orthe number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl,aryl, heteroaryl or heterocyclyl group. That is, the alkyl, alkenyl,alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of thearyl, ring of the heteroaryl or ring of the heterocyclyl can containfrom “a” to “b”, inclusive, carbon atoms. Thus, for example, a “C₁ to C₄alkyl” group refers to all alkyl groups having from 1 to 4 carbons, thatis, CH₃—, CH₃CH₂—, CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)—and (CH₃)₃C—. If no “a” and “b” are designated with regard to an alkyl,alkenyl, alkynyl, cycloalkyl cycloalkenyl, aryl, heteroaryl orheterocyclyl group, the broadest range described in these definitions isto be assumed.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that comprises a fully saturated (no double or triple bonds)hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms(whenever it appears herein, a numerical range such as “1 to 20” refersto each integer in the given range; e.g., “1 to 20 carbon atoms” meansthat the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 20 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 10 carbon atoms. The alkyl group could also be alower alkyl having 1 to 6 carbon atoms. The alkyl group of the compoundsmay be designated as “C₁-C₄ alkyl” or similar designations. By way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl chain, i.e., the alkyl chain is selected from methyl,ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl.Typical alkyl groups include, but are in no way limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl andhexyl. The alkyl group may be substituted or unsubstituted.

As used herein, “alkenyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more double bonds. Analkenyl group may be unsubstituted or substituted.

As used herein, “alkynyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more triple bonds. Analkynyl group may be unsubstituted or substituted.

As used herein, “cycloalkyl” refers to a completely saturated (no doubleor triple bonds) mono- or multi-cyclic hydrocarbon ring system. Whencomposed of two or more rings, the rings may be joined together in afused fashion. Cycloalkyl groups can contain 3 to 10 atoms in thering(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may beunsubstituted or substituted. Typical cycloalkyl groups include, but arein no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

As used herein, “cycloalkenyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more double bonds in atleast one ring; although, if there is more than one, the double bondscannot form a fully delocalized pi-electron system throughout all therings (otherwise the group would be “aryl,” as defined herein). Whencomposed of two or more rings, the rings may be connected together in afused fashion. A cycloalkenyl can contain 3 to 10 atoms in the ring(s)or 3 to 8 atoms in the ring(s). A cycloalkenyl group may beunsubstituted or substituted.

As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclicor multicyclic aromatic ring system (including fused ring systems wheretwo carbocyclic rings share a chemical bond) that has a fullydelocalized pi-electron system throughout all the rings. The number ofcarbon atoms in an aryl group can vary. For example, the aryl group canbe a C₆-C₁₄ aryl group, a C₆-C₁₀ aryl group, or a C₆ aryl group.Examples of aryl groups include, but are not limited to, benzene,naphthalene and azulene. An aryl group may be substituted orunsubstituted.

As used herein, “heteroaryl” refers to a monocyclic, bicyclic andtricyclic aromatic ring system (a ring system with fully delocalizedpi-electron system) that contain(s) one or more heteroatoms (forexample, 1 to 5 heteroatoms), that is, an element other than carbon,including but not limited to, nitrogen, oxygen and sulfur. The number ofatoms in the ring(s) of a heteroaryl group can vary. For example, theheteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atomsin the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term“heteroaryl” includes fused ring systems where two rings, such as atleast one aryl ring and at least one heteroaryl ring, or at least twoheteroaryl rings, share at least one chemical bond. Examples ofheteroaryl rings include, but are not limited to, furan, furazan,thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole,1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole,1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole,indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole,isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline,isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. Aheteroaryl group may be substituted or unsubstituted.

As used herein, “heterocyclyl” or “heteroalicyclyl” refers to three-,four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-memberedmonocyclic, bicyclic and tricyclic ring system wherein carbon atomstogether with from 1 to 5 heteroatoms constitute said ring system. Aheterocycle may optionally contain one or more unsaturated bondssituated in such a way, however, that a fully delocalized pi-electronsystem does not occur throughout all the rings. The heteroatom(s) is anelement other than carbon including, but not limited to, oxygen, sulfurand nitrogen. A heterocycle may further contain one or more carbonyl orthiocarbonyl functionalities, so as to make the definition includeoxo-systems and thio-systems such as lactams, lactones, cyclic imides,cyclic thioimides and cyclic carbamates. When composed of two or morerings, the rings may be joined together in a fused fashion.Additionally, any nitrogens in a heteroalicyclic may be quaternized.Heterocyclyl or heteroalicyclic groups may be unsubstituted orsubstituted. Examples of such “heterocyclyl” or “heteroalicyclyl” groupsinclude but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane,1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane,1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane,1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide,succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine,hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine,imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline,oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine,oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine,pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine,2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran,thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone andtheir benzo-fused analogs (e.g., benzimidazolidinone,tetrahydroquinoline and 3,4-methylenedioxyphenyl).

As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl groupconnected, as a substituent, via a lower alkylene group. The loweralkylene and aryl group of an aryl(alkyl) may be substituted orunsubstituted. Examples include but are not limited to benzyl,2-phenylalkyl, 3-phenylalkyl and naphthylalkyl.

As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to aheteroaryl group connected, as a substituent, via a lower alkylenegroup. The lower alkylene and heteroaryl group of heteroaralkyl may besubstituted or unsubstituted. Examples include but are not limited to2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl,pyridylalkyl, isoxazolylalkyl, imidazolylalkyl and their benzo-fusedanalogs.

A “(heteroalicyclyl)alkyl” and “(heterocyclyl)alkyl” refer to aheterocyclic or a heteroalicyclylic group connected, as a substituent,via a lower alkylene group. The lower alkylene and heterocyclyl of a(heteroalicyclyl)alkyl may be substituted or unsubstituted. Examplesinclude but are not limited tetrahydro-2H-pyran-4-yl)methyl,(piperidin-4-yl)ethyl, (piperidin-4-yl)propyl,(tetrahydro-2H-thiopyran-4-yl)methyl and (1,3-thiazinan-4-yl)methyl.

“Lower alkylene groups” are straight-chained —CH₂— tethering groups,forming bonds to connect molecular fragments via their terminal carbonatoms. Examples include but are not limited to methylene (—CH₂—),ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—) and butylene(—CH₂CH₂CH₂CH₂—). A lower alkylene group can be substituted by replacingone or more hydrogen of the lower alkylene group with a substituent(s)listed under the definition of “substituted.”

As used herein, “alkoxy” refers to the formula —OR wherein R is analkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or(heterocyclyl)alkyl is defined herein. A non-limiting list of alkoxysare methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy maybe substituted or unsubstituted.

As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, oraryl connected, as substituents, via a carbonyl group. Examples includeformyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substitutedor unsubstituted.

As used herein, “hydroxyalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a hydroxy group. Exemplaryhydroxyalkyl groups include but are not limited to, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxypropyl and 2,2-dihydroxyethyl. A hydroxyalkylmay be substituted or unsubstituted.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkyl, di-haloalkyl and tri-haloalkyl). Such groups include butare not limited to, chloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1-chloro-2-fluoromethyl and 2-fluoroisobutyl. Ahaloalkyl may be substituted or unsubstituted.

As used herein, “haloalkoxy” refers to an —O-alkyl group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). Such groups includebut are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. Ahaloalkoxy may be substituted or unsubstituted.

A “sulfenyl” group refers to an “—SR” group in which R can be hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. Asulfenyl may be substituted or unsubstituted.

A “sulfinyl” group refers to an “—S(═O)—R” group in which R can be thesame as defined with respect to sulfenyl. A sulfinyl may be substitutedor unsubstituted.

A “sulfonyl” group refers to an “SO₂R” group in which R can be the sameas defined with respect to sulfenyl. A sulfonyl may be substituted orunsubstituted.

An “O-carboxy” group refers to a “RC(═O)O—” group in which R can behydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or(heterocyclyl)alkyl, as defined herein. An O-carboxy may be substitutedor unsubstituted.

The terms “ester” and “C-carboxy” refer to a “—C(═O)OR” group in which Rcan be the same as defined with respect to O-carboxy. An ester andC-carboxy may be substituted or unsubstituted.

A “thiocarbonyl” group refers to a “—C(═S)R” group in which R can be thesame as defined with respect to O-carboxy. A thiocarbonyl may besubstituted or unsubstituted.

A “trihalomethanesulfonyl” group refers to an “X₃CSO₂—” group whereineach X is a halogen.

A “trihalomethanesulfonamido” group refers to an “X₃CS(O)₂N(R_(A))—”group wherein each X is a halogen, and R_(A) is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,heterocyclyl, aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl.

The term “amino” as used herein refers to a —NH₂ group.

As used herein, the term “hydroxy” refers to a —OH group.

A “cyano” group refers to a “—CN” group.

The term “azido” as used herein refers to a —N₃ group.

An “isocyanato” group refers to a “—NCO” group.

A “thiocyanato” group refers to a “—CNS” group.

An “isothiocyanato” group refers to an “—NCS” group.

A “mercapto” group refers to an “—SH” group.

A “carbonyl” group refers to a C═O group.

An “S-sulfonamido” group refers to a “—SO₂N(R_(A)R_(B))” group in whichR_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),(heteroaryl)alkyl or (heterocyclyl)alkyl. An S-sulfonamido may besubstituted or unsubstituted.

An “N-sulfonamido” group refers to a “RSO₂N(R_(A))—” group in which Rand R_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),(heteroaryl)alkyl or (heterocyclyl)alkyl. An N-sulfonamido may besubstituted or unsubstituted.

An “O-carbamyl” group refers to a “—OC(═O)N(R_(A)R_(B))” group in whichR_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),(heteroaryl)alkyl or (heterocyclyl)alkyl. An O-carbamyl may besubstituted or unsubstituted.

An “N-carbamyl” group refers to an “ROC(═O)N(R_(A))—” group in which Rand R_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),(heteroaryl)alkyl or (heterocyclyl)alkyl. An N-carbamyl may besubstituted or unsubstituted.

An “O-thiocarbamyl” group refers to a “—OC(═S)—N(R_(A)R_(B))” group inwhich R_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl,aryl(alkyl), (heteroaryl)alkyl or (heterocyclyl)alkyl. An O-thiocarbamylmay be substituted or unsubstituted.

An “N-thiocarbamyl” group refers to an “ROC(═S)N(R_(A))—” group in whichR and R_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),(heteroaryl)alkyl or (heterocyclyl)alkyl. An N-thiocarbamyl may besubstituted or unsubstituted.

A “C-amido” group refers to a “—C(═O)N(R_(A)R_(B))” group in which R_(A)and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),(heteroaryl)alkyl or (heterocyclyl)alkyl. A C-amido may be substitutedor unsubstituted.

An “N-amido” group refers to a “RC(═O)N(R_(A))—” group in which R andR_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),(heteroaryl)alkyl or (heterocyclyl)alkyl. An N-amido may be substitutedor unsubstituted.

The term “halogen atom” or “halogen” as used herein, means any one ofthe radio-stable atoms of column 7 of the Periodic Table of theElements, such as, fluorine, chlorine, bromine and iodine.

Where the numbers of substituents is not specified (e.g. haloalkyl),there may be one or more substituents present. For example “haloalkyl”may include one or more of the same or different halogens. As anotherexample, “C₁-C₃ alkoxyphenyl” may include one or more of the same ordifferent alkoxy groups containing one, two or three atoms.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (See, Biochem. 11:942-944(1972)).

The term “nucleoside” is used herein in its ordinary sense as understoodby those skilled in the art, and refers to a compound composed of anoptionally substituted pentose moiety or modified pentose moietyattached to a heterocyclic base or tautomer thereof via a N-glycosidicbond, such as attached via the 9-position of a purine-base or the1-position of a pyrimidine-base. Examples include, but are not limitedto, a ribonucleoside comprising a ribose moiety and adeoxyribonucleoside comprising a deoxyribose moiety. A modified pentosemoiety is a pentose moiety in which an oxygen atom has been replacedwith a carbon and/or a carbon has been replaced with a sulfur or anoxygen atom. A “nucleoside” is a monomer that can have a substitutedbase and/or sugar moiety. Additionally, a nucleoside can be incorporatedinto larger DNA and/or RNA polymers and oligomers. In some instances,the nucleoside can be a nucleoside analog drug.

The term “nucleotide” is used herein in its ordinary sense as understoodby those skilled in the art, and refers to a nucleoside having aphosphate ester bound to the pentose moiety, for example, at the5′-position.

As used herein, the term “heterocyclic base” refers to an optionallysubstituted nitrogen-containing heterocyclyl that can be attached to anoptionally substituted pentose moiety or modified pentose moiety. Insome embodiments, the heterocyclic base can be selected from anoptionally substituted purine-base, an optionally substitutedpyrimidine-base and an optionally substituted triazole-base (forexample, a 1,2,4-triazole). The term “purine-base” is used herein in itsordinary sense as understood by those skilled in the art, and includesits tautomers. Similarly, the term “pyrimidine-base” is used herein inits ordinary sense as understood by those skilled in the art, andincludes its tautomers. A non-limiting list of optionally substitutedpurine-bases includes purine, adenine, guanine, hypoxanthine, xanthine,alloxanthine, 7-alkylguanine (e.g. 7-methylguanine), theobromine,caffeine, uric acid and isoguanine. Examples of pyrimidine-basesinclude, but are not limited to, cytosine, thymine, uracil,5,6-dihydrouracil and 5-alkylcytosine (e.g., 5-methylcytosine). Anexample of an optionally substituted triazole-base is1,2,4-triazole-3-carboxamide. Other non-limiting examples ofheterocyclic bases include diaminopurine, 8-oxo-N⁶-alkyladenine (e.g.,8-oxo-N⁶-methyladenine), 7-deazaxanthine, 7-deazaguanine,7-deazaadenine, N⁴,N⁴-ethanocytosin, N⁶,N⁶-ethano-2,6-diaminopurine,5-halouracil (e.g., 5-fluorouracil and 5-bromouracil),pseudoisocytosine, isocytosine, isoguanine, and other heterocyclic basesdescribed in U.S. Pat. Nos. 5,432,272 and 7,125,855, which areincorporated herein by reference for the limited purpose of disclosingadditional heterocyclic bases. In some embodiments, a heterocyclic basecan be optionally substituted with an amine or an enol protectinggroup(s).

The term “—N-linked amino acid” refers to an amino acid that is attachedto the indicated moiety via a main-chain amino or mono-substituted aminogroup. When the amino acid is attached in an —N-linked amino acid, oneof the hydrogens that is part of the main-chain amino ormono-substituted amino group is not present and the amino acid isattached via the nitrogen. N-linked amino acids can be substituted orunsubstituted.

The term “—N-linked amino acid ester derivative” refers to an amino acidin which a main-chain carboxylic acid group has been converted to anester group. In some embodiments, the ester group has a formula selectedfrom alkyl-O—C(═O)—, cycloalkyl-O—C(═O)—, aryl-O—C(═O)— andaryl(alkyl)-O—C(═O)—. A non-limiting list of ester groups includesubstituted and unsubstituted versions of the following:methyl-O—C(═O)—, ethyl-O—C(═O)—, n-propyl-O—C(═O)—, isopropyl-O—C(═O)—,n-butyl-O—C(═O)—, isobutyl-O—C(═O)—, tert-butyl-O—C(═O)—,neopentyl-O—C(═O)—, cyclopropyl-O—C(═O)—, cyclobutyl-O—C(═O)—,cyclopentyl-O—C(═O)—, cyclohexyl-O—C(═O)—, phenyl-O—C(═O)—,benzyl-O—C(═O)— and naphthyl-O—C(═O)—. N-linked amino acid esterderivatives can be substituted or unsubstituted.

The term “—O-linked amino acid” refers to an amino acid that is attachedto the indicated moiety via the hydroxy from its main-chain carboxylicacid group. When the amino acid is attached in an —O-linked amino acid,the hydrogen that is part of the hydroxy from its main-chain carboxylicacid group is not present and the amino acid is attached via the oxygen.O-linked amino acids can be substituted or unsubstituted.

As used herein, the term “amino acid” refers to any amino acid (bothstandard and non-standard amino acids), including, but not limited to,α-amino acids, β-amino acids, γ-amino acids and δ-amino acids. Examplesof suitable amino acids include, but are not limited to, alanine,asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline,serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, threonine, tryptophan and valine. Additionalexamples of suitable amino acids include, but are not limited to,ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine,gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine,alpha-propyl-glycine and norleucine.

The terms “phosphorothioate” and “phosphothioate” refer to a compound ofthe general formula

its protonated forms (for example,

and its tautomers (such as

As used herein, the term “phosphate” is used in its ordinary sense asunderstood by those skilled in the art, and includes its protonatedforms (for example,

As used herein, the terms “monophosphate,” “diphosphate,” and“triphosphate” are used in their ordinary sense as understood by thoseskilled in the art, and include protonated forms.

The terms “protecting group” and “protecting groups” as used hereinrefer to any atom or group of atoms that is added to a molecule in orderto prevent existing groups in the molecule from undergoing unwantedchemical reactions. Examples of protecting group moieties are describedin T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 3. Ed. John Wiley & Sons, 1999, and in J. F. W. McOmie,Protective Groups in Organic Chemistry Plenum Press, 1973, both of whichare hereby incorporated by reference for the limited purpose ofdisclosing suitable protecting groups. The protecting group moiety maybe chosen in such a way, that they are stable to certain reactionconditions and readily removed at a convenient stage using methodologyknown from the art. A non-limiting list of protecting groups includebenzyl; substituted benzyl; alkylcarbonyls and alkoxycarbonyls (e.g.,t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls andarylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether(e.g. methoxymethyl ether); substituted ethyl ether; a substitutedbenzyl ether; tetrahydropyranyl ether; silyls (e.g., trimethylsilyl,triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl,tri-iso-propylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl ort-butyldiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g.methoxymethylcarbonate); sulfonates (e.g. tosylate or mesylate); acyclicketal (e.g. dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane,1,3-dioxolanes and those described herein); acyclic acetal; cyclicacetal (e.g., those described herein); acyclic hemiacetal; cyclichemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or 1,3-dithiolane);orthoesters (e.g., those described herein) and triarylmethyl groups(e.g., trityl; monomethoxytrityl (MMTr); 4,4′-dimethoxytrityl (DMTr);4,4′,4″-trimethoxytrityl (TMTr); and those described herein).

The term “pharmaceutically acceptable salt” refers to a salt of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, the salt is an acidaddition salt of the compound. Pharmaceutical salts can be obtained byreacting a compound with inorganic acids such as hydrohalic acid (e.g.,hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid andphosphoric acid. Pharmaceutical salts can also be obtained by reacting acompound with an organic acid such as aliphatic or aromatic carboxylicor sulfonic acids, for example formic, acetic, succinic, lactic, malic,tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic,p-toluenesulfonic, salicylic or naphthalenesulfonic acid. Pharmaceuticalsalts can also be obtained by reacting a compound with a base to form asalt such as an ammonium salt, an alkali metal salt, such as a sodium ora potassium salt, an alkaline earth metal salt, such as a calcium or amagnesium salt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C₁-C₇ alkylamine,cyclohexylamine, triethanolamine, ethylenediamine, and salts with aminoacids such as arginine and lysine.

Terms and phrases used in this application, and variations thereof,especially in the appended claims, unless otherwise expressly stated,should be construed as open ended as opposed to limiting. As examples ofthe foregoing, the term ‘including’ should be read to mean ‘including,without limitation,’ ‘including but not limited to,’ or the like; theterm ‘comprising’ as used herein is synonymous with ‘including,’‘containing,’ or ‘characterized by,’ and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps; theterm ‘having’ should be interpreted as ‘having at least;’ the term‘includes’ should be interpreted as ‘includes but is not limited to;’the term ‘example’ is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof; and use of termslike ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words ofsimilar meaning should not be understood as implying that certainfeatures are critical, essential, or even important to the structure orfunction, but instead as merely intended to highlight alternative oradditional features that may or may not be utilized in a particularembodiment. In addition, the term “comprising” is to be interpretedsynonymously with the phrases “having at least” or “including at least”.When used in the context of a process, the term “comprising” means thatthe process includes at least the recited steps, but may includeadditional steps. When used in the context of a compound, composition ordevice, the term “comprising” means that the compound, composition ordevice includes at least the recited features or components, but mayalso include additional features or components. Likewise, a group ofitems linked with the conjunction ‘and’ should not be read as requiringthat each and every one of those items be present in the grouping, butrather should be read as ‘and/of’ unless expressly stated otherwise.Similarly, a group of items linked with the conjunction ‘or’ should notbe read as requiring mutual exclusivity among that group, but rathershould be read as ‘and/or’ unless expressly stated otherwise.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity. The indefinite article “a” or “an” does not exclude aplurality. A single processor or other unit may fulfill the functions ofseveral items recited in the claims. The mere fact that certain measuresare recited in mutually different dependent claims does not indicatethat a combination of these measures cannot be used to advantage. Anyreference signs in the claims should not be construed as limiting thescope.

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, enantiomerically enriched, racemicmixture, diastereomerically pure, diastereomerically enriched, or astereoisomeric mixture. In addition it is understood that, in anycompound described herein having one or more double bond(s) generatinggeometrical isomers that can be defined as E or Z, each double bond mayindependently be E or Z a mixture thereof.

Likewise, it is understood that, in any compound described, alltautomeric forms are also intended to be included. For example alltautomers of a phosphate and a phosphorothioate groups are intended tobe included. Examples of tautomers of a phosphorothioate include thefollowing:

Furthermore, all tautomers of heterocyclic bases known in the art areintended to be included, including tautomers of natural and non-naturalpurine-bases and pyrimidine-bases.

It is to be understood that where compounds disclosed herein haveunfilled valencies, then the valencies are to be filled with hydrogensor isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2(deuterium).

It is understood that the compounds described herein can be labeledisotopically. Substitution with isotopes such as deuterium may affordcertain therapeutic advantages resulting from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements. Each chemical element as represented in a compoundstructure may include any isotope of said element. For example, in acompound structure a hydrogen atom may be explicitly disclosed orunderstood to be present in the compound. At any position of thecompound that a hydrogen atom may be present, the hydrogen atom can beany isotope of hydrogen, including but not limited to hydrogen-1(protium) and hydrogen-2 (deuterium). Thus, reference herein to acompound encompasses all potential isotopic forms unless the contextclearly dictates otherwise.

It is understood that the methods and combinations described hereininclude crystalline forms (also known as polymorphs, which include thedifferent crystal packing arrangements of the same elemental compositionof a compound), amorphous phases, salts, solvates and hydrates. In someembodiments, the compounds described herein exist in solvated forms withpharmaceutically acceptable solvents such as water, ethanol, or thelike. In other embodiments, the compounds described herein exist inunsolvated form. Solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and may be formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, or the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

Compounds

Some embodiments disclosed herein relate to a compound of Formula (I) ora pharmaceutically acceptable salt thereof:

wherein: B¹ can be selected from an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

an optionally substituted

and an optionally substituted

R¹ can be selected from an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₂₋₆ alkenyl, an optionally substituted C₂₋₆alkynyl and an optionally substituted C₃₋₆ cycloalkyl; each

can be absent or a single bond, provided that both

are each absent or both

are each a single bond; when both

are each a single bond, then R² can be halo, N₃, —OR^(7A) or—N(R^(7B)R^(7C)); R⁴ can be absent; R³ can be oxygen (O); and R^(p) canbe

wherein Z^(p) can be oxygen (O) or sulfur (S) and R^(p1) can be selectedfrom O⁻, OH, an —O-optionally substituted C₁₋₆ alkyl.

an optionally substituted N-linked amino acid and an optionallysubstituted N-linked amino acid ester derivative; when both

are each absent, then RP can be absent; R² can be halo, N₃, —OR^(7A) or—N(R^(7B)R^(7C)); R³ can be —OH or —OC(═O)R⁸; or R² and R³ can be eachan oxygen atom which are linked together by a carbonyl group; and R⁴ canbe hydrogen or

R^(5A) can be selected from O⁻, OH, an optionally substituted N-linkedamino acid, an optionally substituted N-linked amino acid esterderivative,

R^(5B) can be selected from O⁻, OH, an —O-optionally substituted aryl,an —O-optionally substituted heteroaryl, an —O-optionally substitutedheterocyclyl, an optionally substituted N-linked amino acid, anoptionally substituted N-linked amino acid ester derivative,

R^(6A) can be an optionally substituted C₁₋₆ alkyl or an optionallysubstituted C₃₋₆ cycloalkyl; R^(6B) and R^(6C) can be independentlyselected from hydrogen, an unsubstituted C₁₋₆ alkyl, an unsubstitutedC₃₋₆ alkenyl, an unsubstituted C₃₋₆ alkynyl and an unsubstituted C₃₋₆cycloalkyl; R^(6D) can be NHR^(6G); R^(6E) can be hydrogen, halogen orNHR^(6H); R^(6F) can be NHR^(6I); R^(6G) can be selected from hydrogen,an optionally substituted C₁₋₆ alkyl, an optionally substituted C₃₋₆alkenyl, an optionally substituted C₃₋₆ cycloalkyl, —C(═O)R^(A1) and—C(═O)OR^(A2); R^(6H) can be selected from hydrogen, an optionallysubstituted C₁₋₆ alkyl, an optionally substituted C₃₋₆ alkenyl, anoptionally substituted C₃₋₆ cycloalkyl, —C(═O)R^(A3) and —C(═O)OR^(A4);R^(6I) can be selected from hydrogen, an optionally substituted C₁₋₆alkyl, an optionally substituted C₃₋₆ alkenyl, an optionally substitutedC₃₋₆ cycloalkyl, —C(═O)R^(A5) and —C(═O)OR^(A6); X¹ can be N (nitrogen)or —CR^(6J), R^(6J) can be selected from hydrogen, halogen, anoptionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆alkenyl and an optionally substituted C₂₋₆ alkynyl; R^(A1), R^(A2),R^(A3), R^(A4), R^(A5) and R^(A6) can be independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkenyl, C₆₋₁₀ aryl, heteroaryl, heterocyclyl, aryl(C₁₋₆ alkyl),heteroaryl(C₁₋₆ alkyl) and heterocyclyl(C₁₋₆ alkyl); R^(7A) can behydrogen or —C(═O)R¹²; R^(7B) and R^(7C) can be independently hydrogenor an optionally substituted C₁₋₆ alkyl; R⁸ and R¹² can be independentlyan optionally substituted C₁₋₆ alkyl or an optionally substituted C₃₋₆cycloalkyl; R⁹, R¹⁰ and R¹¹ can be independently absent or hydrogen;R^(8A), R^(9A), R^(11A), R^(12A), R^(8B), R^(9B), R^(11B), R^(12B),R^(p2), R^(p3), R^(p5) and R^(p6) can be independently selected fromhydrogen, an optionally substituted C₁₋₂₄ alkyl and an optionallysubstituted aryl; R^(10A), R^(10B), R^(13A), R^(13B), R^(p4) and R^(p7)can be independently selected from hydrogen, an optionally substitutedC₁₋₂₄ alkyl, an optionally substituted aryl, an optionally substituted—O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionallysubstituted —O-heteroaryl and an optionally substituted —O-monocyclicheterocyclyl; R^(14A), R^(14B), R^(15A), R^(15B), R^(p8) and R^(p9) canbe independently selected from hydrogen, an optionally substituted C₁₋₂₄alkyl and an optionally substituted aryl; n can be 0 or 1; p, q, and rcan be independently 1 or 2; s, t and u can be independently 3, 4 or 5;Z¹, Z^(1A), Z^(1B) and Z^(p1) can be independently O (oxygen) or S(sulfur); and provided that when R⁴ is

and R^(5A) is O⁻ or OH, then R^(5B) is O⁻, OH,

an optionally substituted N-linked amino acid or an optionallysubstituted N-linked amino acid ester derivative.

The substituents attached to the 2′-carbon can vary. In someembodiments, R² can be halo. For example, R² can be fluoro or chloro. Inother embodiments, R² can be N₃. In some embodiments, R² can be —OH. Inother embodiments, R² can be OR^(7A), wherein R^(7A) can be —C(═O)R¹²,and R¹² can be an optionally substituted C₁₋₆ alkyl. Suitable alkylgroups include, but are not limited to optionally substituted variantsof the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, pentyl (branched and straight-chained) and hexyl (branchedand straight-chained). In yet still other embodiments, R² can beOR^(7A), wherein R^(7A) can be —C(═O)R¹², and R¹² can be an optionallysubstituted C₃₋₆ cycloalkyl. Suitable cycloalkyl groups include, but arenot limited to optionally substituted variants of the following:cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiment,R² can be —N(R^(7B)R^(7C)), wherein R^(7B) and R^(7C) can beindependently hydrogen or an optionally substituted C₁₋₆ alkyl. In someembodiments, R^(7B) and R^(7C) can be both hydrogen, such that R² can be—NH₂. In other embodiments, at least one of R^(7B) and R^(7C) can be anoptionally substituted C₁₋₆ alkyl. In some embodiments, R^(7B) andR^(7C) can be both an optionally substituted C₁₋₆ alkyl. In someembodiments, R^(7B) and R^(7C) can be the same. In other embodiments,R^(7B) and R^(7C) can be different.

Various substituents can be attached to the 3′-carbon of the pentosering. In some embodiments, R³ can be —OH. In other embodiments, R³ canbe —OC(═O)R⁸, wherein R⁸ can be an optionally substituted C₁₋₆ alkylsuch as those described herein. In still other embodiments, R³ can be—OC(═O)R⁸, wherein R⁸ can be an optionally substituted C₃₋₆ cycloalkyl.Examples of suitable optionally substituted C₃₋₆ cycloalkyl groups aredescribed herein.

In some embodiments, R² and R³ can each be an oxygen atom and the oxygenatoms can be linked together by a carbonyl group. In other embodiments,R² and R³ can be both —OH. In other embodiments, R² can be halo and R³can be —OH. In still other embodiments, R² can be halo and R³ can be—OC(═O)R⁸.

In some embodiments, R¹ can be an optionally substituted C₁₋₆ alkyl. Insome embodiments, R¹ can be an unsubstituted C₁₋₆ alkyl. For example, R¹can be unsubstituted methyl, unsubstituted ethyl, unsubstitutedn-propyl, unsubstituted isopropyl, unsubstituted n-butyl, unsubstitutedisobutyl, unsubstituted tert-butyl, unsubstituted pentyl (branched andstraight-chained) or unsubstituted hexyl (branched andstraight-chained). In some embodiments, R¹ can be a substituted C₁₋₆alkyl. Suitable substitutions are described herein. As an example, R¹can be a halo-substituted C₁₋₆ alkyl (such as —CF₃ or —CH₂CH₂F). Inother embodiments, R¹ can be an optionally substituted C₂₋₆ alkenyl.Suitable alkenyl groups include, but are not limited to optionallysubstituted variants of the following: ethenyl, n-propenyl, isopropenyl,n-butenyl, isobutenyl, tert-butenyl, pentenyl (branched andstraight-chained), hexenyl (branched and straight-chained), vinyl andallenyl. In still other embodiments, R¹ can be an optionally substitutedC₂₋₆ alkynyl. In yet still other embodiments, R¹ can be an optionallysubstituted C₃₋₆ cycloalkyl, such as those described herein.

In some embodiments, both

can be each absent, R^(p) can be absent; R² can be halo, N₃, —OR^(7A) or—N(R^(7B)R^(7C)); R³ can be —OH or —OC(═O)R⁸; or R² and R³ can be eachan oxygen atom which are linked together by a carbonyl group; and R⁴ canbe hydrogen or

When both

are absent, Formula (I) can have the structure:

In some embodiments, R⁴ can be hydrogen. In other embodiments, R⁴ can be

In some embodiments, the compound of Formula (I) can be a monophosphate.In other embodiments, the compound of Formula (I) can be athiomonophosphate. In some embodiments, the compound of Formula (I) canbe a diphosphate. In other embodiments, the compound of Formula (I) canbe an alpha-thiodiphosphate. In some embodiments, the compound ofFormula (I) can be a triphosphate. In other embodiments, the compound ofFormula (I) can be an alpha-thiotriphosphate. In some embodiments, R⁴can be

R^(5A) can be O⁻ or OH; and R^(5B) can be O⁻ or OH. In otherembodiments, R⁴ can be

R^(5A) can be O⁻ or OH; R^(5B) can be

and n can be 0. In still other embodiments, R⁴ can be

R^(5A) can be O⁻ or OH; R^(5B) can be

and n can be 1.

The substituents attached to the phosphorus can vary. In someembodiments, a compound of Formula (I) can be a phosphoroamidate. Inother embodiments, a compound of Formula (I) can be athiophosphoroamidate. In still other embodiments, a compound of Formula(I) can be a phosphorbisamidate. In yet still other embodiments, acompound of Formula (I) can be a thiophosphorbisamidate.

In some embodiments, R^(5A) can be an optionally substituted N-linkedamino acid. Various amino acids are suitable, including those describedherein. Examples of suitable amino acids include, but are not limitedto, alanine, asparagine, aspartate, cysteine, glutamate, glutamine,glycine, proline, serine, tyrosine, arginine, histidine, isoleucine,leucine, lysine, methionine, phenylalanine, threonine, tryptophan andvaline. In other embodiments, R^(5A) can be an optionally substitutedN-linked amino acid ester derivative. Examples of N-linked amino acidester derivatives include, but are not limited to, ester derivatives ofany of the following amino acids: alanine, asparagine, aspartate,cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine,arginine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, threonine, tryptophan and valine. Additional examples ofN-linked amino acid ester derivatives include, but are not limited to,an ester derivative of any of the following amino acids:alpha-ethyl-glycine, alpha-propyl-glycine and beta-alanine. In someembodiments, the N-linked amino acid ester derivative can be a C₁₋₆alkyl ester derivative, for example, an isopropyl ester of alanine. Inother embodiments, the N-linked amino acid ester derivative can be aC₃₋₆ cycloalkyl ester derivative, such as a cyclohexyl ester of alanine.

In some embodiments, R^(5A) can have the structure

wherein R¹³ can be selected from hydrogen, an optionally substitutedC₁₋₆-alkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₆ alkyl) and anoptionally substituted haloalkyl; R¹⁴ can be selected from hydrogen, anoptionally substituted C₁₋₆ alkyl, an optionally substituted C₁₋₆haloalkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted C₆ aryl, an optionally substituted C₁₀ aryl and anoptionally substituted aryl(C₁₋₆ alkyl); and R¹⁵ can be hydrogen or anoptionally substituted C₁₋₄-alkyl; or R¹⁴ and R¹⁵ can be taken togetherto form an optionally substituted C₃₋₆ cycloalkyl.

When R¹⁴ is substituted, R¹⁴ can be substituted with one or moresubstituents selected from N-amido, mercapto, alkylthio, an optionallysubstituted aryl, hydroxy, an optionally substituted heteroaryl,O-carboxy and amino. In some embodiments, R¹⁴ can be an unsubstitutedC₁₋₆-alkyl, such as those described herein. In some embodiments, R¹⁴ canbe hydrogen. In other embodiments, R¹⁴ can be methyl. In someembodiments, R¹³ can be an optionally substituted C₁₋₆ alkyl. Examplesof optionally substituted C₁₋₆-alkyls include optionally substitutedvariants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, pentyl (branched and straight-chained) and hexyl(branched and straight-chained). In some embodiments, R¹³ can be methylor isopropyl. In some embodiments, R¹³ can be ethyl or neopentyl. Inother embodiments, R¹³ can be an optionally substituted C₃₋₆ cycloalkyl.Examples of optionally substituted C₃₋₆ cycloalkyl include optionallysubstituted variants of the following: cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. In some embodiments, R¹³ can be anoptionally substituted cyclohexyl. In still other embodiments, R¹³ canbe an optionally substituted aryl, such as phenyl and naphthyl. In yetstill other embodiments, R¹³ can be an optionally substituted aryl(C₁₋₆alkyl). In some embodiments, R¹³ can be an optionally substitutedbenzyl. In some embodiments, R¹³ can be an optionally substituted C₁₋₆haloalkyl, for example, CF₃. In some embodiments, R¹⁵ can be hydrogen.In other embodiments, R¹⁵ can be an optionally substituted C₁₋₄ alkyl,such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl ortert-butyl. In some embodiments, R¹⁵ can be methyl. In some embodiments,R¹⁴ and R¹⁵ can be taken together to form an optionally substituted C₃₋₆cycloalkyl. Examples of optionally substituted C₃₋₆ cycloalkyl includeoptionally substituted variants of the following: cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl. Depending on the groups that areselected for R¹⁴ and R¹⁵, the carbon to which R¹⁴ and R¹⁵ are attachedmay be a chiral center. In some embodiment, the carbon to which R¹⁴ andR¹⁵ are attached may be a (R)-chiral center. In other embodiments, thecarbon to which R¹⁴ and R¹⁵ are attached may be a (S)-chiral center.

Examples of suitable groups include the following:

groups include the following:

In some embodiments, R^(5B) can be an —O-optionally substituted aryl.For example, R^(5B) can be an —O-optionally substituted phenyl. When thephenyl is substituted, the ring can be substituted 1, 2, 3 or more than3 times. Suitable mono-substituted phenyl groups include,ortho-substituted phenyl, meta-substituted phenyl and para-substitutedphenyl. In other embodiments, R^(5B) can be an —O-unsubstituted aryl.Alternatively, R^(5B) can be an —O-optionally substituted naphthyl. Inother embodiments, R^(5B) can be an —O-optionally substitutedheteroaryl. For example, R^(5B) can be an —O-optionally substitutedquinolinyl. In still other embodiments, R^(5B) can be an —O-optionallysubstituted heterocyclyl.

In some embodiments, R^(5B) is an optionally substituted N-linked aminoacid, such as those described for R^(5A). In other embodiments, R^(5B)is an optionally substituted N-linked amino acid ester derivative, forexample, those described herein. In some embodiments, R^(5B) can havethe structure

wherein R¹⁶ can be selected from hydrogen, an optionally substitutedC₁₋₆-alkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₆ alkyl) and anoptionally substituted haloalkyl; R¹⁷ can be selected from hydrogen, anoptionally substituted C₁₋₆ alkyl, an optionally substitutedC₁₋₆haloalkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted C₆ aryl, an optionally substituted C₁₀ aryl and anoptionally substituted aryl(C₁₋₆ alkyl); and R¹⁸ can be hydrogen or anoptionally substituted C₁₋₄-alkyl; or R¹⁷ and R¹⁸ can be taken togetherto form an optionally substituted C₃₋₆ cycloalkyl.

When R¹⁷ is substituted, R¹⁷ can be substituted with one or moresubstituents selected from N-amido, mercapto, alkylthio, an optionallysubstituted aryl, hydroxy, an optionally substituted heteroaryl,O-carboxy and amino. In some embodiments, R¹⁷ can be an unsubstitutedC₁₋₆-alkyl, such as those described herein. In some embodiments, R¹⁷ canbe hydrogen. In other embodiments, R¹⁷ can be methyl. In someembodiments, R¹⁶ can be an optionally substituted C₁₋₆ alkyl. Examplesof optionally substituted C₁₋₆-alkyls include optionally substitutedvariants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, pentyl (branched and straight-chained) and hexyl(branched and straight-chained). In some embodiments, R¹⁶ can be methylor isopropyl. In some embodiments, R¹⁶ can be ethyl or neopentyl. Inother embodiments, R¹⁶ can be an optionally substituted C₃₋₆ cycloalkyl.Examples of optionally substituted C₃₋₆ cycloalkyl include optionallysubstituted variants of the following: cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. In some embodiments, R¹⁶ can be anoptionally substituted cyclohexyl. In still other embodiments, R¹⁶ canbe an optionally substituted aryl, such as phenyl and naphthyl. In yetstill other embodiments, R¹⁶ can be an optionally substituted aryl(C₁₋₆alkyl). In some embodiments, R¹⁶ can be an optionally substitutedbenzyl. In some embodiments, R¹⁶ can be an optionally substituted C₁₋₆haloalkyl, for example, CF₃. In some embodiments, R¹⁸ can be hydrogen.In other embodiments, R¹⁸ can be an optionally substituted C₁₋₄-alkyl,such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl ortert-butyl. In some embodiments, R¹⁸ can be methyl. In some embodiments,R¹⁷ and R¹⁸ can be taken together to form an optionally substituted C₃₋₆cycloalkyl. Examples of optionally substituted C₃₋₆ cycloalkyl includeoptionally substituted variants of the following: cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl. Depending on the groups that areselected for R¹⁷ and R¹⁸, the carbon to which R¹⁷ and R¹⁸ are attachedmay be a chiral center. In some embodiment, the carbon to which R¹⁷ andR¹⁸ are attached may be a (R)-chiral center. In other embodiments, thecarbon to which R¹⁷ and R¹⁸ are attached may be a (S)-chiral center.

Examples of suitable

groups include the following:

In some embodiments, R^(5A) can be an optionally substituted N-linkedamino acid or an optionally substituted N-linked amino acid esterderivative and R^(5B) can be an —O-optionally substituted aryl. In otherembodiments, R^(5A) can be an optionally substituted N-linked amino acidor an optionally substituted N-linked amino acid ester derivative andR^(5B) can be an —O-optionally substituted heteroaryl. In someembodiments, R^(5A) can be an optionally substituted N-linked amino acidor an optionally substituted N-linked amino acid ester derivative andR^(5A) can be an optionally substituted N-linked amino acid or anoptionally substituted N-linked amino acid ester derivative.

In some embodiments, R^(5A) can be

When R^(5A) is

R^(8A) and R^(9A) can be independently selected from hydrogen, anoptionally substituted C₁₋₂₄ alkyl and an optionally substituted aryl;and R^(10A) can be selected from hydrogen, an optionally substitutedC₁₋₂₄ alkyl, an optionally substituted aryl, an optionally substituted—O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionallysubstituted —O-heteroaryl and an optionally substituted —O-monocyclicheterocyclyl. In some embodiments, R^(8A) and R^(9A) can be hydrogen. Inother embodiments, at least one of R^(8A) and R^(9A) can be anoptionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl. Insome embodiments, R^(19A) can be hydrogen. In other embodiments, R^(19A)can be an optionally substituted C₁₋₂₄ alkyl. In some embodiments,R^(19A) can be an unsubstituted C₁₋₄ alkyl. In still other embodiments,R^(19A) can be an optionally substituted aryl. In yet still otherembodiments, R^(19A) can be —O—C₁₋₂₄ alkyl, an optionally substituted—O-aryl, an optionally substituted —O-heteroaryl or an optionallysubstituted —O-monocyclic heterocyclyl. In some embodiments, R^(19A) canbe an unsubstituted —O—C₁₋₄ alkyl.

In some embodiments, R^(5B) can be

When R^(5B) is

R^(8B) and R^(9B) can be independently selected from hydrogen, anoptionally substituted C₁₋₂₄ alkyl and an optionally substituted aryl;and R^(10B) can be selected from hydrogen, an optionally substitutedC₁₋₂₄ alkyl, an optionally substituted aryl, an optionally substituted—O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionallysubstituted —O— heteroaryl and an optionally substituted —O-monocyclicheterocyclyl. In some embodiments, R^(8B) and R^(9B) can be hydrogen. Inother embodiments, at least one of R^(8B) and R^(9B) can be anoptionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl. Insome embodiments, R^(10B) can be hydrogen. In other embodiments, R^(10B)can be an optionally substituted C₁₋₂₄ alkyl. In some embodiments,R^(10B) can be an unsubstituted C₁₋₄ alkyl. In still other embodiments,R^(10B) can be an optionally substituted aryl. In yet still otherembodiments, R^(10B) can be —O—C₁₋₂₄ alkyl, an optionally substituted—O-aryl, an optionally substituted —O-heteroaryl or an optionallysubstituted —O-monocyclic heterocyclyl. In some embodiments, R^(10B) canbe an unsubstituted —O—C₁₋₄ alkyl. In some embodiments, R^(5A) can be

and R^(5B) can be

In some embodiments, R^(5A) can be

wherein R^(11A) and R^(12A) can be independently selected from hydrogen,an optionally substituted C₁₋₂₄ alkyl and an optionally substitutedaryl; R^(13A) can be independently selected from hydrogen, an optionallysubstituted C₁₋₂₄ alkyl, an optionally substituted aryl, an optionallysubstituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, anoptionally substituted —O-heteroaryl and an optionally substituted—O-monocyclic heterocyclyl; and Z^(1A) can be independently O (oxygen)or S (sulfur). In some embodiments, R^(11A) and R^(12A) can be hydrogen.In other embodiments, at least one of R^(11A) and R^(12A) can be anoptionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl. Insome embodiments, R^(10A) can be an optionally substituted C₁₋₂₄ alkyl.In some embodiments, R^(13A) can be an unsubstituted C₁₋₄ alkyl. Inother embodiments, R^(10A) can be an optionally substituted aryl. Instill other embodiments, R^(13A) can be an optionally substituted—O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionallysubstituted —O-heteroaryl or an optionally substituted —O-monocyclicheterocyclyl. In some embodiments, R^(13A) can be an unsubstituted—O—C₁₋₄ alkyl. In some embodiments, Z^(1A) can be O (oxygen). In otherembodiments, Z^(IA) can be or S (sulfur).

In some embodiments, R^(5B) can be

wherein R^(11B) and R^(12B) can be independently selected from hydrogen,an optionally substituted C₁₋₂₄ alkyl and an optionally substitutedaryl; R^(13B) can be independently selected from hydrogen, an optionallysubstituted C₁₋₂₄ alkyl, an optionally substituted aryl, an optionallysubstituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, anoptionally substituted —O-heteroaryl and an optionally substituted—O-monocyclic heterocyclyl; and Z^(1B) can be independently O (oxygen)or S (sulfur). In some embodiments, R^(13B) and R^(12B) can be hydrogen.In other embodiments, at least one of R^(11B) and R^(12B) can be anoptionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl. Insome embodiments, R^(13B) can be an optionally substituted C₁₋₂₄ alkyl.In some embodiments, R^(13B) can be an unsubstituted C₁₋₄ alkyl. Inother embodiments, R^(13B) can be an optionally substituted aryl. Instill other embodiments, R^(13B) can be an optionally substituted—O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionallysubstituted —O-heteroaryl or an optionally substituted —O-monocyclicheterocyclyl. In some embodiments, R^(13B) can be an unsubstituted—O—C₁₋₄ alkyl. In some embodiments, Z^(1B) can be O (oxygen). In otherembodiments, Z^(1B) can be or S (sulfur). In some embodiments, R^(5A)can be

and R^(5B) can be

In some embodiments, R^(5A) can be

In some embodiments, R^(14A) can be hydrogen. In other embodiments,R^(14A) can be an optionally substituted C₁₋₂₄ alkyl. In still otherembodiments, R^(14A) can be an optionally substituted aryl. In someembodiments, R^(14A) can be a C₁₋₆ alkyl, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In someembodiments, p can be 1. In other embodiments, p can be 2.

In some embodiments, R^(5B) can be

In some embodiments, R^(14B) can be hydrogen. In other embodiments,R^(14B) can be an optionally substituted C₁₋₂₄ alkyl. In still otherembodiments, R^(14B) can be an optionally substituted aryl. In someembodiments, R^(14B) can be a C₁₋₆ alkyl, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In someembodiments, q can be 1. In other embodiments, q can be 2. In someembodiments, R^(5A) can be

and R^(5B) can be

In some embodiments, R^(5A) can be

In some embodiments, R^(15A) can be hydrogen. In other embodiments,R^(15A) can be an optionally substituted C₁₋₂₄ alkyl. In still otherembodiments, R^(15A) can be an optionally substituted aryl, for example,an optionally substituted phenyl. In some embodiments, R^(15A) can be anoptionally substituted C₁₋₆ alkyl. In some embodiments, R^(15A) can bean unsubstituted C₁₋₆ alkyl. In some embodiments, s can be 3. In otherembodiments, s can be 4. In still other embodiments, s can be 5.

In some embodiments, R^(5B) can be

In some embodiments, R^(15B) can be hydrogen. In other embodiments,R^(15B) can be an optionally substituted C₁₋₂₄ alkyl. In still otherembodiments, R^(15B) can be an optionally substituted aryl, for example,an optionally substituted phenyl. In some embodiments, R^(15B) can be anoptionally substituted C₁₋₆ alkyl. In some embodiments, R^(15B) can bean unsubstituted C₁₋₆ alkyl. In some embodiments, t can be 3. In otherembodiments, t can be 4. In still other embodiments, t can be 5. In someembodiments, R^(5A) can be

and R^(5B) can be

In some embodiments, R^(5A) and/or R^(5B) can beisopropyloxycarbonyloxymethoxy (POC) group. In some embodiments, R^(5A)and/or R^(5B) can be pivaloyloxymethoxy (POM) group. In someembodiments, R^(5A) and R^(5B) can be both aisopropyloxycarbonyloxymethoxy (POC) group, and form abis(isopropyloxycarbonyloxymethoxy) (bis(POC)) prodrug. In otherembodiments, R^(5A) and R^(5B) can be both a pivaloyloxymethoxy (POM)group, and form a bis(pivaloyloxymethoxy) (bis(POM)) prodrug. In stillother embodiments, R^(5A) and R^(5B) can be both a S-acylthioethyl(SATE)-O— group and form a SATE ester prodrug. In some embodiments,R^(5A) and R^(5B) can be the same. In other embodiments, R^(5A) andR^(5B) can be different.

In some embodiments, both

can be each a single bond; R⁴ can be absent; R³ can be oxygen (O); andR^(p) can be

wherein Z^(p) can be oxygen (O) or sulfur (S) and R^(p1) can be selectedfrom O⁻, OH, an —O-optionally substituted C₁₋₆ alkyl.

an optionally substituted N-linked amino acid and an optionallysubstituted N-linked amino acid ester derivative. When both

are each a single bond, Formula (I) can have the structure:

In some embodiments, R^(p1) can be O⁻. In other embodiments, R^(p1) canbe OH. In other embodiments, R^(p1) can be an —O-optionally substitutedC₁₋₆ alkyl. For example, R^(p1) can be a substituted or an unsubstitutedversion of the following: methoxy, ethoxy, n-propoxy, iso-propoxy,n-butoxy, iso-butoxy, tert-butoxy, pentoxy (branched or straightchained) and hexoxy (branched or straight chained).

In some embodiments, R^(p1) can be

wherein R^(p2) and R_(p3) can be independently selected from hydrogen,an optionally substituted C₁₋₂₄ alkyl and an optionally substitutedaryl; and R^(p4) can be selected from hydrogen, an optionallysubstituted C₁₋₂₄ alkyl, an optionally substituted aryl, an optionallysubstituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, anoptionally substituted —O-heteroaryl and an optionally substituted—O-monocyclic heterocyclyl. In some embodiments, R^(p2) and R^(p3) canbe hydrogen. In other embodiments, at least one of R^(p2) and R^(p3) canbe an optionally substituted C₁₋₂₄ alkyl or an optionally substitutedaryl. In some embodiments, R^(p4) can be an optionally substituted C₁₋₂₄alkyl. In some embodiments, R^(p4) can be an unsubstituted C₁₋₄ alkyl.In other embodiments, R^(p4) can be an optionally substituted aryl. Instill other embodiments, R^(p4) can be an optionally substituted—O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionallysubstituted —O-heteroaryl or an optionally substituted —O-monocyclicheterocyclyl. In some embodiments, R^(p4) can be an unsubstituted—O—C₁₋₄ alkyl.

In some embodiments, R^(p1) can be

wherein R^(p5) and R^(p6) can be independently selected from hydrogen,an optionally substituted C₁₋₂₄ alkyl and an optionally substitutedaryl; R^(p7) can be independently selected from hydrogen, an optionallysubstituted C₁₋₂₄ alkyl, an optionally substituted aryl, an optionallysubstituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, anoptionally substituted —O-heteroaryl and an optionally substituted—O-monocyclic heterocyclyl; and Z^(p1) can be independently O (oxygen)or S (sulfur). In some embodiments, R^(p5) and R^(p6) can be hydrogen.In other embodiments, at least one of R^(p5) and R^(p6) can be anoptionally substituted C₁₋₂₄ alkyl or an optionally substituted aryl. Insome embodiments, R^(p7) can be an optionally substituted C₁₋₂₄ alkyl.In some embodiments, R^(p7) can be an unsubstituted C₁₋₄ alkyl. In otherembodiments, R^(p7) can be an optionally substituted aryl. In stillother embodiments, R^(p7) can be an optionally substituted —O—C₁₋₂₄alkyl, an optionally substituted —O-aryl, an optionally substituted—O-heteroaryl or an optionally substituted —O-monocyclic heterocyclyl.In some embodiments, R^(p7) can be an unsubstituted —O—C₁₋₄ alkyl. Insome embodiments, Z^(p1) can be O (oxygen). In other embodiments, Z^(p1)can be or S (sulfur). In some embodiments, R^(p1) can beisopropyloxycarbonyloxymethyloxy (POC) group. In some embodiments,R^(p1) can be pivaloyloxymethyloxy (POM) group.

In some embodiments, R^(p1) can be

In some embodiments, R^(p1) can be hydrogen. In other embodiments,R^(p8) can be an optionally substituted C₁₋₂₄ alkyl. In still otherembodiments, R^(p8) can be an optionally substituted aryl. In someembodiments, R^(p8) can be a C₁₋₆ alkyl, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In someembodiments, r can be 1. In other embodiments, r can be 2.

In some embodiments, R^(p1) can be

In some embodiments, R^(p9) can be hydrogen. In other embodiments,R^(p9) can be an optionally substituted C₁₋₂₄ alkyl. In still otherembodiments, R^(p9) can be an optionally substituted aryl, for example,an optionally substituted phenyl. In some embodiments, R^(p9) can be anoptionally substituted C₁₋₆ alkyl. In some embodiments, R^(p9) can be anunsubstituted C₁₋₆ alkyl. In some embodiments, u can be 3. In otherembodiments, u can be 4. In still other embodiments, u can be 5. In someembodiments, R^(p1) can be a S-acylthioethyl (SATE) group and form aSATE ester prodrug.

In some embodiments, R^(p1) can be an optionally substituted N-linkedamino acid or an optionally substituted N-linked amino acid esterderivative. For example, R^(p1) can be optionally substituted version ofthe following: alanine, asparagine, aspartate, cysteine, glutamate,glutamine, glycine, proline, serine, tyrosine, arginine, histidine,isoleucine, leucine, lysine, methionine, phenylalanine, threonine,tryptophan, valine and ester derivatives thereof. In some embodiments,R^(p1) can be selected from N-alanine isopropyl ester, N-alaninecyclohexyl ester, N-alanine neopentyl ester, N-valine isopropyl esterand N-leucine isopropyl ester. In some embodiments, R^(p1) can have thestructure

wherein R^(p10) can be selected from hydrogen, an optionally substitutedC₁₋₆-alkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₆ alkyl) and anoptionally substituted haloalkyl; R^(p11) can be selected from hydrogen,an optionally substituted C₁₋₆ alkyl, an optionally substituted C₁₋₆haloalkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted C₆ aryl, an optionally substituted C₁₀ aryl and anoptionally substituted aryl(C₁₋₆ alkyl); and R^(p12) can be hydrogen oran optionally substituted C₁₋₄-alkyl; or R^(p11) and R^(p12) can betaken together to form an optionally substituted C₃₋₆ cycloalkyl.

When R^(p11) is substituted, R^(p11) can be substituted with one or moresubstituents selected from N-amido, mercapto, alkylthio, an optionallysubstituted aryl, hydroxy, an optionally substituted heteroaryl,O-carboxy, and amino. In some embodiments, R^(p11) can be anunsubstituted C₁₋₆-alkyl, such as those described herein. In someembodiments, R^(p11) can be hydrogen. In other embodiments, R^(p11) canbe methyl. In some embodiments, R^(p10) can be an optionally substitutedC₁₋₆ alkyl. Examples of optionally substituted C₁₋₆-alkyls includeoptionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained), and hexyl (branched and straight-chained). In someembodiments, R^(p10) can be methyl or isopropyl. In some embodiments,R^(p10) can be ethyl or neopentyl. In other embodiments, R^(p10) can bean optionally substituted C₃₋₆ cycloalkyl. Examples of optionallysubstituted C₃₋₆ cycloalkyl include optionally substituted variants ofthe following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Insome embodiments, R^(p10) can be an optionally substituted cyclohexyl.In still other embodiments, R^(p10) can be an optionally substitutedaryl, such as phenyl and naphthyl. In yet still other embodiments,R^(p10) can be an optionally substituted aryl(C₁₋₆ alkyl). In someembodiments, R^(p10) can be an optionally substituted benzyl. In someembodiments, R^(p10) can be an optionally substituted C₁₋₆ haloalkyl,for example, CF₃. In some embodiments, R^(p12) can be hydrogen. In otherembodiments, R^(p12) can be an optionally substituted C₁₋₄-alkyl, suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.In some embodiments, R^(p12) can be methyl. In some embodiments, R^(p11)and R^(p12) can be taken together to form an optionally substituted C₃₋₆cycloalkyl. Examples of optionally substituted C₃₋₆ cycloalkyl includeoptionally substituted variants of the following: cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl. Depending on the groups thatare selected for R^(p11) and R^(p12), the carbon to which R^(p11) andR^(p12) are attached may be a chiral center. In some embodiment, thecarbon to which R^(p11) and R^(p12) are attached may be a (R)-chiralcenter. In other embodiments, the carbon to which R^(p11) and R^(p12)are attached may be a (S)-chiral center.

Examples of suitable

groups include the following:

The nucleobase can vary. In some embodiments, B¹ can be uracil. In someembodiments, B¹ can be an optionally substituted

In some embodiments, B¹ can be unsubstituted

In other embodiments, B¹ can be an optionally substituted

In some embodiments, B¹ can be unsubstituted

In some embodiments, R^(6A) can be an optionally substituted C₁₋₆ alkyl.For example, R^(6A) can be methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, pentyl (branched and straight-chained) or hexyl(branched and straight-chained). In other embodiments, R^(6A) can be anoptionally substituted C₃₋₆ cycloalkyl, for example, optionallysubstituted variants of the following: cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

In some embodiments, B can be guanine. In some embodiments, B can be anoptionally substituted

In other embodiments, B¹ can be an optionally substituted

wherein R^(6B) can be selected from hydrogen, an unsubstituted C₁₋₆alkyl, an unsubstituted C₃₋₆ alkenyl, an unsubstituted C₃₋₆ alkynyl andan unsubstituted C₃₋₆ cyclo alkyl. In some embodiments, B¹ can beunsubstituted

In some embodiments, R^(6B) can be an unsubstituted C₁₋₆ alkyl. Forexample, R^(6B) can be methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, pentyl (branched and straight-chained) or hexyl(branched and straight-chained). In some embodiments, R^(6B) can be anunsubstituted C₃₋₆ alkenyl. In other embodiments, R^(6B) can be anunsubstituted C₃₋₆ alkynyl. In still other embodiments, R^(6B) can be anunsubstituted C₃₋₆ cycloalkyl, for example, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

In some embodiments, B¹ can be an optionally substituted

wherein R^(6C) can be selected from hydrogen, an unsubstituted C₁₋₆alkyl, an unsubstituted C₃₋₆ alkenyl, an unsubstituted C₃₋₆ alkynyl andan unsubstituted C₃₋₆ cycloalkyl. In some embodiments, B¹ can beunsubstituted

In some embodiments, R^(6C) can be hydrogen. In some embodiments, R^(6C)can be an unsubstituted C₁₋₆ alkyl. For example, R^(6C) can be methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl(branched and straight-chained) or hexyl (branched andstraight-chained). In some embodiments, R^(6C) can be an ethyl. In someembodiments, R^(6C) can be an unsubstituted C₃₋₆ alkenyl. In otherembodiments, R^(6C) can be an unsubstituted C₃₋₆ alkynyl. In otherembodiments, R^(6C) can be an unsubstituted C₃₋₆ cycloalkyl, forexample, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some embodiments, B¹ can be adenine. In some embodiments, B¹ can bean optionally substituted

wherein X¹ can be N (nitrogen) or —CR^(6J); R^(6J) can be selected fromhydrogen, halogen, an optionally substituted C₁₋₆ alkyl, an optionallysubstituted C₂₋₆ alkenyl and an optionally substituted C₂₋₆ alkynyl;R^(6D) can be NHR^(6G); R^(6E) can be hydrogen, halogen or NHR^(6H);R^(6G) can be selected from hydrogen, an optionally substituted C₁₋₆alkyl, an optionally substituted C₃₋₆ alkenyl, an optionally substitutedC₃₋₆ cycloalkyl, —C(═O)R^(A1) and —C(═O)OR^(A2); R^(6H) can be selectedfrom hydrogen, an optionally substituted C₁₋₆ alkyl, an optionallysubstituted C₃₋₆ alkenyl, an optionally substituted C₃₋₆ cycloalkyl,—C(═O)R^(A3) and —C(═O)OR^(A4); R^(A1), R^(A2), R^(A3) and R^(A4) can beindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkenyl, C₆₋₁₀ aryl, heteroaryl, heterocyclyl,aryl(C₁₋₆ alkyl), heteroaryl(C₁₋₆ alkyl) and heterocyclyl(C₁₋₆ alkyl).In some embodiments, X¹ can be N (nitrogen). In other embodiments, X¹can be —CR^(6I), wherein CR^(6I) can be selected from hydrogen, halogen,an optionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆alkenyl and an optionally substituted C₂₋₆ alkynyl. In some embodiments,X¹ can be CH. In some embodiments, R^(6D) and R^(6E) can be both NH₂. Inother embodiments, at least one of R^(6D) and R^(6E) can be NH₂. In someembodiments, R^(6D) can be NHR^(6G), wherein R^(6G) can be an optionallysubstituted C₁₋₆ alkyl. In some embodiments, R^(6E) can be hydrogen. Inother embodiments, R^(6E) can be halogen. In still other embodiments,R^(6E) can be NHR^(6H), wherein R^(6H) can be an optionally substitutedC₁₋₆ alkyl. In other embodiments, R^(6D) can be NHR^(6G), wherein R^(6G)can be selected from an optionally substituted C₃₋₆ alkenyl, anoptionally substituted C₃₋₆ cycloalkyl, —C(═O)R^(A1) and —C(═O)OR^(A2).In other embodiments, R^(6E) can be NHR^(6H), wherein R^(6H) can beselected from an optionally substituted C₃₋₆ alkenyl, an optionallysubstituted C₃₋₆ cycloalkyl, —C(═O)R^(A3) and —C(═O)OR^(A4). In someembodiments, R^(6D) and R^(6E) can be the same. In other embodiments,R^(6D) and R^(6E) can be different.

In some embodiments, B¹ can be cytosine. In some embodiments, B¹ can bean optionally substituted

wherein R^(6F) can be NHR^(6I); R^(6I) can be selected hydrogen, anoptionally substituted C₁₋₆ alkyl, an optionally substituted C₃₋₆alkenyl, an optionally substituted C₃₋₆ cycloalkyl, —C(═O)R^(A5) and—C(═O)OR^(A6); and R^(A5) and R^(A6) are independently selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkenyl, C₆₋₁₀ aryl, heteroaryl, heterocyclyl,aryl(C₁₋₆ alkyl), heteroaryl(C₁₋₆ alkyl) and heterocyclyl(C₁₋₆ alkyl).In some embodiments, R^(6F) can be NH₂. In other embodiments, R^(6F) canbe NHR^(6I), wherein R^(6I) can be an optionally substituted C₁₋₆ alkyl,an optionally substituted C₃₋₆ alkenyl or an optionally substituted C₃₋₆cycloalkyl. In still other embodiments, R^(6F) can be NHR^(6I), whereinR^(6I) can be —C(═O)R^(A5) or —C(═O)OR^(A6). When R^(6I) is —C(═O)R^(A5)or —C(═O)OR^(A6), R^(A5) and R^(A6) can be C₁₋₆ alkyl, C₂₋₆ alkenyl orC₂₋₆ alkynyl. and R^(A6) can also be C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl,C₆₋₁₀ aryl or heteroaryl, heterocyclyl. Additionally, R^(A5) and R^(A6)can be aryl(C₁₋₆ alkyl), heteroaryl(C₁₋₆ alkyl) or heterocyclyl(C₁₋₆alkyl).

In some embodiments, Z¹ can be O (oxygen). In other embodiments, Z¹ canbe S (sulfur).

In some embodiments, R² is not halo. In some embodiments, R² is notfluoro. In some embodiments, R^(5B) is not an —O-optionally substitutedaryl. In some embodiments, R^(5B) is not an —O-unsubstituted aryl. Insome embodiments, R^(5A) is not N-alanine isopropyl ester. In someembodiments, R¹ is not an optionally substituted C₁₋₆ alkyl. Forexample, R¹ is not an unsubstituted C₁₋₆ alkyl, such as methyl. In someembodiments, B¹ is not an optionally substituted uracil, for example, ahalo-substituted uracil. In some embodiment, when both

are each absent; R^(P) is absent; R³ is OH or —OC(═O)R⁸; R² is F; and R¹is methyl, ethyl or ethenyl; then R⁴ cannot be selected from H and

wherein R^(5B) is an —O-unsubstituted aryl; R^(5A) is

and Z¹ is oxygen. In some embodiments, R² is not halo (such as fluoro)when B¹ is uracil. In some embodiments, a compound of Formula (I) is nota compound in WO 2013/092481 (filed Dec. 17, 2012).

Example structures of a compound of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing. In someembodiments of this paragraph, R³ can be OH. In some embodiments of thisparagraph, R^(6C) can be an unsubstituted C₁₋₆ alkyl, such as CH₂CH₃. Insome embodiments of this paragraph, R^(p1) can be —O-unsubstituted C₁₋₆alkyl. In some embodiments, of this paragraph, R⁴ can be H. In otherembodiments, of this paragraph, R⁴ can be a phosphoroamidate group. Instill other embodiments, of this paragraph, R⁴ can be a phosphate group(such as a mono-, di- or tri-phosphate). In yet still other embodiments,of this paragraph, R⁴ can be a thiophosphoroamidate group. In someembodiments, of this paragraph, R⁴ can be thiophosphate group (such asan alpha-thiomono-, alpha-thiodi- or alpha-thiotri-phosphate). In someembodiments of this paragraph, R^(p1) can be —O-ethyl, —O-isopropyl or—O-isobutyl.

Examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

Additional examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

Still further examples of compounds of Formula (I) include thefollowing:

or a pharmaceutically acceptable salt of the foregoing.

Examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

Further examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

Further examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

Additional examples of compounds of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

In some embodiments, a compound of Formula (I) cannot be selected from:

or a pharmaceutically acceptable salt of the foregoing.

As described herein, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can have R⁴ being

R^(5A) being an optionally substituted N-linked amino acid or anoptionally substituted N-linked amino acid ester derivative; and R^(5B)being an —O-optionally substituted aryl, an —O-optionally substitutedheteroaryl, an —O-optionally substituted heterocyclyl, an optionallysubstituted N-linked amino acid or an optionally substituted N-linkedamino acid ester derivative. By neutralizing the charge on the phosphateor thiophosphate, penetration of the cell membrane may be facilitated asa result of the increased lipophilicity of the compound. Once absorbedand taken inside the cell, the groups attached to the phosphorus can beeasily removed by esterases, proteases and/or other enzymes. In someembodiments, the groups attached to the phosphorus can be removed bysimple hydrolysis. Inside the cell, the phosphate thus released may thenbe metabolized by cellular enzymes to the diphosphate or the activetriphosphate. Likewise, the thio-phosphate may be metabolized to thealpha-thiodiphosphate or the alpha-thiotriphosphate. Furthermore, insome embodiments, varying the substituents on a compound describedherein, such as compound of Formula (I), can help maintain the efficacyof such the compound by reducing undesirable effects, such asisomerization.

In some embodiments, the phosphorylation of a thio-monophosphate of acompound of Formula (I), or pharmaceutically acceptable salt thereof,can be stereoselective. For example, a thio-monophosphate of a compoundof Formula (I) can be phosphorylated to give an alpha-thiodiphosphateand/or an alpha-thiotriphosphate compound that can be enriched in the(R) or (S) diastereomer with respect to the 5′-O-phosphorous atom. Forexample, one of the (R) and (S) configuration with respect to the5′-O-phosphorous atom of the alpha-thiodiphosphate and/or thealpha-thiotriphosphate compound can be present in an amount >50%, ≧75%,≧90%, ≧95% or ≧99% compared to the amount of the other of the (R) or (S)configuration with respect to the 5′-O-phosphorous atom. In someembodiments, phosphorylation of a compound of Formula (I), orpharmaceutically acceptable salt thereof, can result in the formation ofa compound that has the (R)-configuration at the 5′-O-phosphorous atom.In some embodiments, phosphorylation of a compound of Formula (I), orpharmaceutically acceptable salt thereof, can result in formation of acompound that has the (S)-configuration at the 5′-O-phosphorous atom.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can act as a chain terminator of HCVreplication. For example, compounds of Formula (I) can contain a moietyat the 2′-carbon position such that once the compound is incorporatedinto an RNA chain of HCV no further elongation is observed to occur. Forexample, a compound of Formula (I) can contain a 2′-carbon modificationwherein is a non-hydrogen group selected from an optionally substitutedC₁₋₆ alkyl, an optionally substituted C₂₋₆ alkenyl, an optionallysubstituted C₂₋₆ alkynyl and an optionally substituted C₃₋₆ cycloalkyl.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can have increased metabolic and/or plasmastability. In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be more resistant tohydrolysis and/or more resistant to enzymatic transformations. Forexample, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, can have increased metabolic stability, increased plasmastability, can be more resistant to hydrolysis and/or can be moreresistant to enzymatic transformations compared to a compound that isidentical in structure but for having a hydrogen in place of the fluoroat the 4′-position. In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can have improved properties.A non-limiting list of example properties include, but are not limitedto, increased biological half-life, increased bioavailability, increasepotency, a sustained in vivo response, increased dosing intervals,decreased dosing amounts, decreased cytotoxicity, reduction in requiredamounts for treating disease conditions, reduction in viral load,reduction in time to seroconversion (i.e., the virus becomesundetectable in patient serum), increased sustained viral response, areduction of morbidity or mortality in clinical outcomes, increasedsubject compliance, decreased liver conditions (such as liver fibrosis,liver cirrhosis and/or liver cancer), and compatibility with othermedications. In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can have a biologicalhalf-life of greater than 24 hours. In some embodiments, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, can have abiological half-life greater than a compound that is identical instructure but for having a hydrogen in place of the fluoro at the4′-position. In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can have more potent antiviralactivity (for example, a lower EC₅₀ in an HCV replicon assay) ascompared to the current standard of care. In some embodiments, acompound of Formula (I), or a pharmaceutically acceptable salt thereof,does not significantly inhibit mitochondrial function of themitochondrial RNA polymerase. For example, a compound of Formula (I), ora pharmaceutically acceptable salt thereof, is incorporated in the humanmitochondrial RNA polymerase less than 10% compared to the natural5′-triphosphate nucleotide with the same B¹.

Additionally, in some embodiments, the presence of athiophosphoroamidate, phosphoroamidate, thiophosphorbisamidate orphosphorbisamidate in a compound of Formula (I) can increase thestability of the compound by inhibiting its degradation. Also, in someembodiments, the presence of a thiophosphoroamidate, phosphoroamidate,thiophosphorbisamidate or phosphorbisamidate can make the compound moreresistant to cleavage in vivo and provide sustained, extended efficacy.In some embodiments, a thiophosphoroamidate, phosphoroamidate,thiophosphorbisamidate or phosphorbisamidate can facilitate thepenetration of the cell membrane by a compound of Formula (I) by makingthe compound more lipophilic. In some embodiments, athiophosphoroamidate, phosphoroamidate, thiophosphorbisamidate orphosphorbisamidate can have improved oral bioavailability, improvedaqueous stability and/or reduced risk of byproduct-related toxicity. Insome embodiments, for comparison purposes, a compound of Formula (I) canbe compared to a compound that is identical in structure but for havinga hydrogen in place of the fluoro at the 4′-position.

Synthesis

Compounds of Formula (I) and those described herein may be prepared invarious ways. General synthetic routes to the compound of Formula (I),and some examples of starting materials used to synthesize the compoundsof Formula (I) are shown in Scheme 1 and 2, and described herein. Theroutes shown and described herein are illustrative only and are notintended, nor are they to be construed, to limit the scope of the claimsin any manner whatsoever. Those skilled in the art will be able torecognize modifications of the disclosed syntheses and to devisealternate routes based on the disclosures herein; all such modificationsand alternate routes are within the scope of the claims.

Compounds of Formula (I) can be prepared using various methods known tothose skilled in the art. Examples of methods are shown in Schemes 1 and2. Suitable phosphorus containing precursors can be commerciallyobtained or prepared by synthetic methods known to those skilled in theart. Examples of general structures of phosphorus containing precursorsare shown in Schemes 1 and 2, and include phosphorochloridates andthiophosphorochloridates. Suitable phosphorochloridates andthiophosphorochloridates are commercially available and/or can besynthetically prepared.

One method for forming a compound of Formula (I) is shown in Scheme 1.In Scheme 1, R^(1a), R^(2a), R^(3a) and B^(1a) can be the same as R¹,R², R³ and B¹ as described herein for Formula (I). In some embodiments,a compound of Formula (I) can be generated from a compound of Formula(A) and a compound of Formula (B) or a compound of Formula (A) and acompound of Formula (C) using an organometallic reagent, such as aGrignard reagent. Suitable Grignard reagents are known to those skilledin the art and include, but are not limited to, alkylmagnesium chloridesand alkylmagnesium bromides. In other embodiments, an appropriate basecan be used to form a compound of Formula (I). Examples of suitablebases include, but are not limited to, an amine base, such as analkylamine (including mono-, di- and tri-alkylamines (e.g.,triethylamine)), optionally substituted pyridines (e.g. collidine) andoptionally substituted imidazoles (e.g., N-methylimidazole)).

When compounds of Formula (I) has Z¹ being sulfur, the sulfur can beadded in various manners. In some embodiments, the sulfur can be part ofthe phosphorus containing precursor, for example,

Alternatively, one of the oxygens attached to the phosphorus can beexchanged with a sulfur using a sulfurization reagent. Suitablesulfurization agents are known to those skilled in the art, and include,but are not limited to, elemental sulfur, Lawesson's reagent,cyclooctasulfur, 3H-1,2-Benzodithiole-3-one-1, 1-dioxide (Beaucage'sreagent),3-((N,N-dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-5-thione(DDTT) and bis(3-triethoxysilyl)propyl-tetrasulfide (TEST).

A phosphorus containing precursor can be coupled to the nucleoside, forexample, a compound of Formula (A). Following the coupling of thephosphorus containing precursor, any leaving groups can be cleaved undersuitable conditions, such as hydrolysis. In Scheme 2, R^(1a), R^(2a),R^(3a) and B^(1a) can be the same as R¹, R², R³ and B¹ as describedherein for Formula (I). Further phosphorus containing groups can beadded using methods known to those skilled in the art, for example usinga pyrophosphate. If desired, one or more bases can be used during theaddition of each phosphorus-containing group. Examples of suitable basesare described herein.

As described herein, in some embodiments, R² and R³ can be each anoxygen atom, wherein the oxygen atoms are linked together by a carbonylgroups. The —O—C(═O)—O— group can be formed using methods known to thoseskilled in the art. For example, a compound of Formula (I), wherein R²and R³ are both hydroxy groups, can be treated with 1,1′-carbonyldiimidazole (CDI).

In some embodiments, R² and/or R³ can be —OC(═O)R¹² and —OC(═O)R⁸,respectively. The —OC(═O)R¹² and —OC(═O)R⁸ groups can be formed at the2′- and 3′-positions using various methods known to those skilled in theart. As an example, a compound of Formula (I), wherein R² and R³ areboth hydroxy groups, can be treated with an alkyl anhydride (e.g.,acetic anhydride and propionic anhydride) or an alkyl acid chloride(e.g., acetylchloride). If desired, a catalyst can be used to facilitatethe reaction. An example of suitable catalyst is 4-dimethylaminopyridine(DMAP). Alternatively, the —OC(═O)R¹² and —OC(═O)R⁸ groups can be formedat the 2′- and 3′-positions by reacting an alkyl acid (e.g. acetic acidand propionic acid) in the presences of a carbodiimide or a couplingreagent. Examples of carbodiimides include, but are not limited to,N,N′-dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide (DIC)and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC).

To reduce the formation of side products, one or more the groupsattached to the pentose ring can be protected with one or more suitableprotecting groups. As an example, if R² and/or R³ is/are hydroxygroup(s), the hydroxy group(s) can be protected with suitable protectinggroups, such as triarylmethyl and/or silyl groups. Examples oftriarylmethyl groups include but are not limited to, trityl,monomethoxytrityl (MMTr), 4,4′-dimethoxytrityl (DMTr),4,4′,4″-trimethoxytrityl (TMTr), 4,4′,4″-tris-(benzoyloxy) trityl(TBTr), 4,4′,4″-tris (4,5-dichlorophthalimido) trityl (CPTr),4,4′,4″-tris (levulinyloxy) trityl (TLTr),p-anisyl-1-naphthylphenylmethyl, di-o-anisyl-1-naphthylmethyl,p-tolyldipheylmethyl, 3-(imidazolylmethyl)-4,4′-dimethoxytrityl,9-phenylxanthen-9-yl (Pixyl), 9-(p-methoxyphenyl) xanthen-9-yl (Mox),4-decyloxytrityl, 4-hexadecyloxytrityl, 4,4′-dioctadecyltrityl,9-(4-octadecyloxyphenyl) xanthen-9-yl,1,1′-bis-(4-methoxyphenyl)-1′-pyrenylmethyl,4,4,4″-tris-(tert-butylphenyl) methyl (TTTr) and4,4′-di-3,5-hexadienoxytrityl. Examples of suitable silyl groups aredescribed herein and include trimethylsilyl (TMS),tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS),tert-butyldiphenylsilyl (TBDPS), tri-iso-propylsilyloxymethyl and[2-(trimethylsilyl)ethoxy]methyl. Alternatively, R² and/or R³ can beprotected by a single achiral or chiral protecting group, for example,by forming an orthoester, a cyclic acetal or a cyclic ketal. Suitableorthoesters include methoxymethylene acetal, ethoxymethylene acetal,2-oxacyclopentylidene orthoester, dimethoxymethylene orthoester,1-methoxyethylidene orthoester, 1-ethoxyethylidene orthoester,methylidene orthoester, phthalide orthoester 1,2-dimethoxyethylideneorthoester, and alpha-methoxybenzylidene orthoester; suitable cyclicacetals include methylene acetal, ethylidene acetal, t-butylmethylideneacetal, 3-(benzyloxy)propyl acetal, benzylidene acetal,3,4-dimethoxybenzylidene acetal and p-acetoxybenzylidene acetal; andsuitable cyclic ketals include 1-t-butylethylidene ketal,1-phenylethylidene ketal, isopropylidene ketal, cyclopentylidene ketal,cyclohexylidene ketal, cycloheptylidene ketal and1-(4-methoxyphenyl)ethylidene ketal.

Pharmaceutical Compositions

Some embodiments described herein relates to a pharmaceuticalcomposition, that can include an effective amount of one or morecompounds described herein (e.g., a compound of Formula (I)), or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable carrier, diluent, excipient or combination thereof. In someembodiments, the pharmaceutical composition can include a singlediastereomer of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, (for example, a single diastereomer is presentin the pharmaceutical composition at a concentration of greater than 99%compared to the total concentration of the other diastereomers). Inother embodiments, the pharmaceutical composition can include a mixtureof diastereomers of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof. For example, the pharmaceutical composition caninclude a concentration of one diastereomer of >50%, ≧60%, ≧70%, ≧80%,≧90%, ≧95%, or ≧98%, as compared to the total concentration of the otherdiastereomers. In some embodiments, the pharmaceutical compositionincludes a 1:1 mixture of two diastereomers of a compound of Formula(I), or a pharmaceutically acceptable salt thereof.

The term “pharmaceutical composition” refers to a mixture of one or morecompounds disclosed herein with other chemical components, such asdiluents or carriers. The pharmaceutical composition facilitatesadministration of the compound to an organism. Pharmaceuticalcompositions can also be obtained by reacting compounds with inorganicor organic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonicacid, p-toluenesulfonic acid and salicylic acid. Pharmaceuticalcompositions will generally be tailored to the specific intended routeof administration. A pharmaceutical composition is suitable for humanand/or veterinary applications.

The term “physiologically acceptable” defines a carrier, diluent orexcipient that does not abrogate the biological activity and propertiesof the compound.

As used herein, a “carrier” refers to a compound that facilitates theincorporation of a compound into cells or tissues. For example, withoutlimitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrierthat facilitates the uptake of many organic compounds into cells ortissues of a subject.

As used herein, a “diluent” refers to an ingredient in a pharmaceuticalcomposition that lacks pharmacological activity but may bepharmaceutically necessary or desirable. For example, a diluent may beused to increase the bulk of a potent drug whose mass is too small formanufacture and/or administration. It may also be a liquid for thedissolution of a drug to be administered by injection, ingestion orinhalation. A common form of diluent in the art is a buffered aqueoussolution such as, without limitation, phosphate buffered saline thatmimics the composition of human blood.

As used herein, an “excipient” refers to an inert substance that isadded to a pharmaceutical composition to provide, without limitation,bulk, consistency, stability, binding ability, lubrication,disintegrating ability etc., to the composition. A “diluent” is a typeof excipient.

The pharmaceutical compositions described herein can be administered toa human patient per se, or in pharmaceutical compositions where they aremixed with other active ingredients, as in combination therapy, orcarriers, diluents, excipients or combinations thereof. Properformulation is dependent upon the route of administration chosen.Techniques for formulation and administration of the compounds describedherein are known to those skilled in the art.

The pharmaceutical compositions disclosed herein may be manufactured ina manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or tableting processes. Additionally, theactive ingredients are contained in an amount effective to achieve itsintended purpose. Many of the compounds used in the pharmaceuticalcombinations disclosed herein may be provided as salts withpharmaceutically compatible counterions.

Multiple techniques of administering a compound exist in the artincluding, but not limited to, oral, rectal, topical, aerosol, injectionand parenteral delivery, including intramuscular, subcutaneous,intravenous, intramedullary injections, intrathecal, directintraventricular, intraperitoneal, intranasal and intraocularinjections.

One may also administer the compound in a local rather than systemicmanner, for example, via injection of the compound directly into theinfected area, often in a depot or sustained release formulation.Furthermore, one may administer the compound in a targeted drug deliverysystem, for example, in a liposome coated with a tissue-specificantibody. The liposomes will be targeted to and taken up selectively bythe organ.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. The pack or dispensermay also be accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, may be the labeling approvedby the U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. Compositions that can include a compounddescribed herein formulated in a compatible pharmaceutical carrier mayalso be prepared, placed in an appropriate container, and labeled fortreatment of an indicated condition.

Methods of Use

Some embodiments disclosed herein relate to a method of treating and/orameliorating a disease or condition that can include administering to asubject an effective amount of one or more compounds described herein,such as a compound of Formula (I), or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition that includes a compounddescribed herein, or a pharmaceutically acceptable salt thereof. Otherembodiments disclosed herein relate to a method of treating and/orameliorating a disease or condition that can include administering to asubject identified as suffering from the disease or condition aneffective amount of one or more compounds described herein, such as acompound of Formula (I), or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition that includes a compound describedherein, or a pharmaceutically acceptable salt thereof.

Some embodiments disclosed herein relates to a method of ameliorating ortreating a HCV infection that can include administering to a subjectidentified as suffering from a HCV infection an effective amount of oneor more compounds described herein (for example, a compound of Formula(I)), or a pharmaceutical composition that includes one or morecompounds described herein, or a pharmaceutically acceptable saltthereof. Other embodiments described herein relate to using one or morecompounds described herein, or a pharmaceutically acceptable salt of acompound described herein, in the manufacture of a medicament forameliorating and/or treating a HCV infection that can includeadministering to a subject identified as suffering from a HCV infectionan effective amount of one or more compounds described herein. Stillother embodiments described herein relate to one or more compoundsdescribed herein, or a pharmaceutically acceptable salt of a compounddescribed herein, that can be used for ameliorating and/or treating aHCV infection by administering to a subject identified as suffering froma HCV infection an effective amount of one or more compounds describedherein.

Some embodiments disclosed herein relate to methods of amelioratingand/or treating a HCV infection that can include contacting a cellinfected with the hepatitis C virus with an effective amount of one ormore compounds described herein, or a pharmaceutically acceptable saltof a compound described herein, or a pharmaceutical composition thatincludes one or more compounds described herein, or a pharmaceuticallyacceptable salt thereof. Other embodiments described herein relate tousing one or more compounds described herein, or a pharmaceuticallyacceptable salt of a compound described herein, in the manufacture of amedicament for ameliorating and/or treating a HCV infection that caninclude contacting a cell infected with the hepatitis C virus with aneffective amount of said compound(s). Still other embodiments describedherein relate to one or more compounds described herein, or apharmaceutically acceptable salt of a compound described herein, thatcan be used for ameliorating and/or treating a HCV infection bycontacting a cell infected with the hepatitis C virus with an effectiveamount of said compound(s).

Some embodiments disclosed herein relate to methods of inhibitingreplication of a hepatitis C virus that can include contacting a cellinfected with the hepatitis C virus with an effective amount of one ormore compounds described herein, or a pharmaceutically acceptable saltof a compound described herein, or a pharmaceutical composition thatincludes one or more compounds described herein, or a pharmaceuticallyacceptable salt thereof. Other embodiments described herein relate tousing one or more compounds described herein, or a pharmaceuticallyacceptable salt of a compound described herein, in the manufacture of amedicament for inhibiting replication of a hepatitis C virus that caninclude contacting a cell infected with the hepatitis C virus with aneffective amount of said compound(s). Still other embodiments describedherein relate to a compound described herein, or a pharmaceuticallyacceptable salt of a compound described herein, that can be used forinhibiting replication of a hepatitis C virus by contacting a cellinfected with the hepatitis C virus with an effective amount of saidcompound(s).

In some embodiments, the compound can be a compound of Formula (I), or apharmaceutical acceptable salt thereof, wherein R⁴ is hydrogen. In otherembodiments, the compound can be a compound of Formula (I), whereincompound of Formula (I) is a mono, di, or triphosphate, or apharmaceutically acceptable salt of the foregoing. In still otherembodiments, the compound can be a compound of Formula (I), whereincompound of Formula (I) is a thiomonophosphate, alpha-thiodiphosphate,or alpha-thiotriphosphate, or a pharmaceutically acceptable salt of theforegoing. In yet still other embodiments, the compound can be acompound of Formula (I), wherein compound of Formula (I) isphosphoroamidate or phosphorbisamidate, or a pharmaceutically acceptablesalt of the foregoing. In some embodiments, the compound can be acompound of Formula (I), wherein compound of Formula (I) isthiophosphoroamidate or thiophosphorbisamidate, or a pharmaceuticallyacceptable salt of the foregoing. In some embodiments, the compound ofFormula (I), or a pharmaceutical acceptable salt thereof, that can beused to ameliorating and/or treating a viral infection (for example, aHCV infection) and/or inhibit replication of a virus (such as a HCVvirus) can be any of the embodiments provided in any of the embodimentsdescribed in paragraphs [0090]-[0138].

HCV is an enveloped positive strand RNA virus in the Flaviviridaefamily. There are various nonstructural proteins of HCV, such as NS2,NS3, NS4, NS4A, NS4B, NS5A and NS5B. NS5B is believed to be anRNA-dependent RNA polymerase involved in the replication of HCV RNA.

Some embodiments described herein relate to a method of inhibiting NS5Bpolymerase activity that can include contacting a cell infected withhepatitis C virus with an effective amount of a compound of Formula (I),or a pharmaceutical acceptable salt thereof. Some embodiments describedherein relate to a method of inhibiting NS5B polymerase activity thatcan include administering to a subject infected with hepatitis C virusan effective amount of a compound of Formula (I), or a pharmaceuticalacceptable salt thereof. In some embodiments, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, can inhibit a RNAdependent RNA polymerase, and thus, inhibit the replication of HCV RNA.In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can inhibit a HCV polymerase (for example, NS5Bpolymerase).

Some embodiments described herein relate to a method of treating acondition selected from liver fibrosis, liver cirrhosis and liver cancerin a subject suffering from one or more of the aforementioned liverconditions that can include administering to the subject an effectiveamount of a compound or a pharmaceutical composition described herein(for example, a compound of Formula (I), or a pharmaceutical acceptablesalt thereof), wherein the liver condition is caused by a HCV infection.Some embodiments described herein relate to a method of increasing liverfunction in a subject having a HCV infection that can includeadministering to the subject an effective amount of a compound or apharmaceutical composition described herein (for example, a compound ofFormula (I), or a pharmaceutical acceptable salt thereof). Alsocontemplated is a method for reducing or eliminating furthervirus-caused liver damage in a subject having an HCV infection byadministering to the subject an effective amount of a compound or apharmaceutical composition described herein (for example, a compound ofFormula (I), or a pharmaceutical acceptable salt thereof). In someembodiments, this method can include slowing or halting the progressionof liver disease. In other embodiments, the course of the disease can bereversed, and stasis or improvement in liver function is contemplated.In some embodiments, liver fibrosis, liver cirrhosis and/or liver cancercan be treated; liver function can be increased; virus-caused liverdamage can be reduced or eliminated; progression of liver disease can beslowed or halted; the course of the liver disease can be reversed and/orliver function can be improved or maintained by contacting a cellinfected with hepatitis C virus with an effective amount of a compounddescribed herein (for example, a compound of Formula (I), or apharmaceutically acceptable salt thereof.)

There are a variety of genotypes of HCV, and a variety of subtypeswithin each genotype. For example, at present it is known that there areeleven (numbered 1 through 11) main genotypes of HCV, although othershave classified the genotypes as 6 main genotypes. Each of thesegenotypes is further subdivided into subtypes (1a-1c; 2a-2c; 3a-3b;4a-4e; 5a; 6a; 7a-7b; 8a-8b; 9a; 10a; and 11a). In some embodiments, aneffective amount of a compound of Formula (I), or a pharmaceuticalacceptable salt thereof, or a pharmaceutical composition that includesan effective amount of a compound of Formula (I), or a pharmaceuticalacceptable salt thereof, can be effective to treat at least one genotypeof HCV. In some embodiments, a compound described herein (for example, acompound of Formula (I), or a pharmaceutical acceptable salt thereof)can be effective to treat all 11 genotypes of HCV. In some embodiments,a compound described herein (for example, a compound of Formula (I), ora pharmaceutical acceptable salt thereof) can be effective to treat 3 ormore, 5 or more, 7 or more, or 9 or more genotypes of HCV. In someembodiments, a compound of Formula (I), or a pharmaceutical acceptablesalt thereof can be more effective against a larger number of HCVgenotypes than the standard of care. In some embodiments, a compound ofFormula (I), or a pharmaceutical acceptable salt thereof, can be moreeffective against a particular HCV genotype than the standard of care(such as genotype 1, 2, 3, 4, 5 and/or 6).

Various indicators for determining the effectiveness of a method fortreating a HCV infection are known to those skilled in the art. Examplesof suitable indicators include, but are not limited to, a reduction inviral load, a reduction in viral replication, a reduction in time toseroconversion (virus undetectable in patient serum), an increase in therate of sustained viral response to therapy, a reduction of morbidity ormortality in clinical outcomes, a reduction in the rate of liverfunction decrease; stasis in liver function; improvement in liverfunction; reduction in one or more markers of liver dysfunction,including alanine transaminase, aspartate transaminase, total bilirubin,conjugated bilirubin, gamma glutamyl transpeptidase and/or otherindicator of disease response. Similarly, successful therapy with aneffective amount of a compound or a pharmaceutical composition describedherein (for example, a compound of Formula (I), or a pharmaceuticalacceptable salt thereof) can reduce the incidence of liver cancer in HCVinfected subjects.

In some embodiments, an effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, is an amount that iseffective to reduce HCV viral titers to undetectable levels, forexample, to about 100 to about 500, to about 50 to about 100, to about10 to about 50, or to about 15 to about 25 international units/mL serum.In some embodiments, an effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, is an amount that iseffective to reduce HCV viral load compared to the HCV viral load beforeadministration of the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof. For example, wherein the HCV viral load ismeasured before administration of the compound of Formula (I), or apharmaceutically acceptable salt thereof, and again after completion ofthe treatment regime with the compound of Formula (I), or apharmaceutically acceptable salt thereof (for example, 1 month aftercompletion). In some embodiments, an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, can be anamount that is effective to reduce HCV viral load to lower than about 25international units/mL serum. In some embodiments, an effective amountof a compound of Formula (I), or a pharmaceutically acceptable saltthereof, is an amount that is effective to achieve a reduction in HCVviral titer in the serum of the subject in the range of about 1.5-log toabout a 2.5-log reduction, about a 3-log to about a 4-log reduction, ora greater than about 5-log reduction compared to the viral load beforeadministration of the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof. For example, the HCV viral load can be measuredbefore administration of the compound of Formula (I), or apharmaceutically acceptable salt thereof, and again after completion ofthe treatment regime with the compound of Formula (I), or apharmaceutically acceptable salt thereof (for example, 1 month aftercompletion).

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can result in at least a 1, 2, 3, 4, 5, 10, 15,20, 25, 50, 75, 100-fold or more reduction in the replication of thehepatitis C virus relative to pre-treatment levels in a subject, asdetermined after completion of the treatment regime (for example, 1month after completion). In some embodiments, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, can result in a reductionof the replication of the hepatitis C virus relative to pre-treatmentlevels in the range of about 2 to about 5 fold, about 10 to about 20fold, about 15 to about 40 fold, or about 50 to about 100 fold. In someembodiments, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, can result in a reduction of the hepatitis C virusreplication in the range of 1 to 1.5 log, 1.5 log to 2 log, 2 log to 2.5log, 2.5 to 3 log, 3 log to 3.5 log or 3.5 to 4 log more reduction ofthe hepatitis C virus replication compared to the reduction of thehepatitis C virus reduction achieved by pegylated interferon incombination with ribavirin, administered according to the standard ofcare, or may achieve the same reduction as that standard of care therapyin a shorter period of time, for example, in one month, two months, orthree months, as compared to the reduction achieved after six months ofstandard of care therapy with ribavirin and pegylated interferon.

In some embodiments, an effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, is an amount that iseffective to achieve a sustained viral response, for example,non-detectable or substantially non-detectable HCV RNA (e.g., less thanabout 500, less than about 200, less than about 100, less than about 25,or less than about 15 international units per milliliter serum) is foundin the subject's serum for a period of at least about one month, atleast about two months, at least about three months, at least about fourmonths, at least about five months, or at least about six monthsfollowing cessation of therapy.

In some embodiments, an effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, can reduce a level of amarker of liver fibrosis by at least about 10%, at least about 20%, atleast about 25%, at least about 30%, at least about 35%, at least about40%, at least about 45%, at least about 50%, at least about 55%, atleast about 60%, at least about 65%, at least about 70%, at least about75%, or at least about 80%, or more, compared to the level of the markerin an untreated subject, or to a placebo-treated subject. Methods ofmeasuring serum markers are known to those skilled in the art andinclude immunological-based methods, e.g., enzyme-linked immunosorbentassays (ELISA), radioimmunoassays, and the like, using antibody specificfor a given serum marker. A non-limiting list of examples of markersincludes measuring the levels of serum alanine aminotransferase (ALT),aspartate aminotransferase (AST), alkaline phosphatase (ALP),gamma-glutamyl transpeptidase (GGT) and total bilirubin (TBIL) usingknown methods. In general, an ALT level of less than about 45 IU/L(international units/liter), an AST in the range of 10-34 IU/L, ALP inthe range of 44-147 IU/L, GGT in the range of 0-51 IU/L, TBIL in therange of 0.3-1.9 mg/dL is considered normal. In some embodiments, aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can be an amount effective to reduce ALT, AST,ALP, GGT and/or TBIL levels to with what is considered a normal level.

Subjects who are clinically diagnosed with HCV infection include “naïve”subjects (e.g., subjects not previously treated for HCV, particularlythose who have not previously received IFN-alpha-based and/orribavirin-based therapy) and individuals who have failed prior treatmentfor HCV (“treatment failure” subjects). Treatment failure subjectsinclude “non-responders” (i.e., subjects in whom the HCV titer was notsignificantly or sufficiently reduced by a previous treatment for HCV(≦0.5 log IU/mL), for example, a previous IFN-alpha monotherapy, aprevious IFN-alpha and ribavirin combination therapy, or a previouspegylated IFN-alpha and ribavirin combination therapy); and “relapsers”(i.e., subjects who were previously treated for HCV, for example, whoreceived a previous IFN-alpha monotherapy, a previous IFN-alpha andribavirin combination therapy, or a previous pegylated IFN-alpha andribavirin combination therapy, whose HCV titer decreased, andsubsequently increased).

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can be administered to a treatment failuresubject suffering from HCV. In some embodiments, a compound of Formula(I), or a pharmaceutically acceptable salt thereof, can be administeredto a non-responder subject suffering from HCV. In some embodiments, acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be administered to a relapsed subject suffering from HCV.

After a period of time, infectious agents can develop resistance to oneor more therapeutic agents. The term “resistance” as used herein refersto a viral strain displaying a delayed, lessened and/or null response toa therapeutic agent(s). For example, after treatment with an antiviralagent, the viral load of a subject infected with a resistant virus maybe reduced to a lesser degree compared to the amount in viral loadreduction exhibited by a subject infected with a non-resistant strain.In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can be administered to a subject infected withan HCV strain that is resistant to one or more different anti-HCV agents(for example, an agent used in a conventional standard of care). In someembodiments, development of resistant HCV strains is delayed when asubject is treated with a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, compared to the development of HCV strainsresistant to other HCV drugs (such as an agent used in a conventionalstandard of care).

In some embodiments, an effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, can be administered to asubject for whom other anti-HCV medications are contraindicated. Forexample, administration of pegylated interferon alpha in combinationwith ribavirin is contraindicated in subjects with hemoglobinopathies(e.g., thalassemia major, sickle-cell anemia) and other subjects at riskfrom the hematologic side effects of current therapy. In someembodiments, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, can be provided to a subject that is hypersensitive tointerferon and/or ribavirin.

Some subjects being treated for HCV experience a viral load rebound. Theterm “viral load rebound” as used herein refers to a sustained ≧0.5 logIU/mL increase of viral load above nadir before the end of treatment,where nadir is a ≧0.5 log IU/mL decrease from baseline. In someembodiments, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, can be administered to a subject experiencing viral loadrebound, or can prevent such viral load rebound when used to treat thesubject.

The standard of care for treating HCV has been associated with severalside effects (adverse events). In some embodiments, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, can decreasethe number and/or severity of side effects that can be observed in HCVpatients being treated with ribavirin and pegylated interferon accordingto the standard of care. Examples of side effects include, but are notlimited to fever, malaise, tachycardia, chills, headache, arthralgias,myalgias, fatigue, apathy, loss of appetite, nausea, vomiting, cognitivechanges, asthenia, drowsiness, lack of initiative, irritability,confusion, depression, severe depression, suicidal ideation, anemia, lowwhite blood cell counts, and thinning of hair. In some embodiments, acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be provided to a subject that discontinued a HCV therapy because ofone or more adverse effects or side effects associated with one or moreother HCV agents (for example, an agent used in a conventional standardof care).

Table 1 provides some embodiments of the percentage improvement obtainedusing a compound of Formula (I), or a pharmaceutically acceptable saltthereof, as compared to the standard of care. Examples include thefollowing: in some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, results in a percentage ofnon-responders that is 10% less than the percentage of non-respondersreceiving the standard of care; in some embodiments, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, results in anumber of side effects that is in the range of about 10% to about 30%less than compared to the number of side effects experienced by asubject receiving the standard of care; and in some embodiments, acompound of Formula (I), or a pharmaceutically acceptable salt thereof,results in a severity of a side effect (such as one of those describedherein) that is 25% less than compared to the severity of the same sideeffect experienced by a subject receiving the standard of care. Methodsof quantifying the severity of a side effect are known to those skilledin the art.

TABLE 1 Percentage Percentage Percentage Percentage Number Severity ofnon- of of of viral of side of side responders relapsers resistance loadrebound effects effects 10% less 10% less 10% less 10% less 10% less 10%less 25% less 25% less 25% less 25% less 25% less 25% less 40% less 40%less 40% less 40% less 40% less 40% less 50% less 50% less 50% less 50%less 50% less 50% less 60% less 60% less 60% less 60% less 60% less 60%less 70% less 70% less 70% less 70% less 70% less 70% less 80% less 80%less 80% less 80% less 80% less 80% less 90% less 90% less 90% less 90%less 90% less 90% less about 10% about 10% about 10% about 10% about 10%about 10% to about to about to about to about to about to about 30% less30% less 30% less 30% less 30% less 30% less about 20% about 20% about20% about 20% about 20% about 20% to about to about to about to about toabout to about 50% less 50% less 50% less 50% less 50% less 50% lessabout 30% about 30% about 30% about 30% about 30% about 30% to about toabout to about to about to about to about 70% less 70% less 70% less 70%less 70% less 70% less about 20% about 20% about 20% about 20% about 20%about 20% to about to about to about to about to about to about 80% less80% less 80% less 80% less 80% less 80% less

As used herein, a “subject” refers to an animal that is the object oftreatment, observation or experiment. “Animal” includes cold- andwarm-blooded vertebrates and invertebrates such as fish, shellfish,reptiles and, in particular, mammals. “Mammal” includes, withoutlimitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats,cows, horses, primates, such as monkeys, chimpanzees, and apes, and, inparticular, humans. In some embodiments, the subject is human.

As used herein, the terms “treating,” “treatment,” “therapeutic,” or“therapy” do not necessarily mean total cure or abolition of the diseaseor condition. Any alleviation of any undesired signs or symptoms of adisease or condition, to any extent can be considered treatment and/ortherapy. Furthermore, treatment may include acts that may worsen thepatient's overall feeling of well-being or appearance.

The terms “therapeutically effective amount” and “effective amount” areused to indicate an amount of an active compound, or pharmaceuticalagent, that elicits the biological or medicinal response indicated. Forexample, an effective amount of compound can be the amount needed toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated This response may occur in atissue, system, animal or human and includes alleviation of the signs orsymptoms of the disease being treated. Determination of an effectiveamount is well within the capability of those skilled in the art, inview of the disclosure provided herein. The effective amount of thecompounds disclosed herein required as a dose will depend on the routeof administration, the type of animal, including human, being treated,and the physical characteristics of the specific animal underconsideration. The dose can be tailored to achieve a desired effect, butwill depend on such factors as weight, diet, concurrent medication andother factors which those skilled in the medical arts will recognize.

As will be readily apparent to one skilled in the art, the useful invivo dosage to be administered and the particular mode of administrationwill vary depending upon the age, weight, the severity of theaffliction, and mammalian species treated, the particular compoundsemployed, and the specific use for which these compounds are employed.The determination of effective dosage levels, that is the dosage levelsnecessary to achieve the desired result, can be accomplished by oneskilled in the art using routine methods, for example, human clinicaltrials and in vitro studies.

The dosage may range broadly, depending upon the desired effects and thetherapeutic indication. Alternatively dosages may be based andcalculated upon the surface area of the patient, as understood by thoseof skill in the art. Although the exact dosage will be determined on adrug-by-drug basis, in most cases, some generalizations regarding thedosage can be made. The daily dosage regimen for an adult human patientmay be, for example, an oral dose of between 0.01 mg and 3000 mg of eachactive ingredient, preferably between 1 mg and 700 mg, e.g. 5 to 200 mg.The dosage may be a single one or a series of two or more given in thecourse of one or more days, as is needed by the subject. In someembodiments, the compounds will be administered for a period ofcontinuous therapy, for example for a week or more, or for months oryears. In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be administered lessfrequently compared to the frequency of administration of an agentwithin the standard of care. In some embodiments, a compound of Formula(I), or a pharmaceutically acceptable salt thereof, can be administeredone time per day. For example, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be administered one timeper day to a subject suffering from a HCV infection. In someembodiments, the total time of the treatment regime with a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, can lesscompared to the total time of the treatment regime with the standard ofcare.

In instances where human dosages for compounds have been established forat least some condition, those same dosages may be used, or dosages thatare between about 0.1% and 500%, more preferably between about 25% and250% of the established human dosage. Where no human dosage isestablished, as will be the case for newly-discovered pharmaceuticalcompositions, a suitable human dosage can be inferred from ED₅₀ or ID₅₀values, or other appropriate values derived from in vitro or in vivostudies, as qualified by toxicity studies and efficacy studies inanimals.

In cases of administration of a pharmaceutically acceptable salt,dosages may be calculated as the free base. As will be understood bythose of skill in the art, in certain situations it may be necessary toadminister the compounds disclosed herein in amounts that exceed, oreven far exceed, the above-stated, preferred dosage range in order toeffectively and aggressively treat particularly aggressive diseases orinfections.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain themodulating effects, or minimal effective concentration (MEC). The MECwill vary for each compound but can be estimated from in vitro data.Dosages necessary to achieve the MEC will depend on individualcharacteristics and route of administration. However, HPLC assays orbioassays can be used to determine plasma concentrations. Dosageintervals can also be determined using MEC value. Compositions should beadministered using a regimen which maintains plasma levels above the MECfor 10-90% of the time, preferably between 30-90% and most preferablybetween 50-90%. In cases of local administration or selective uptake,the effective local concentration of the drug may not be related toplasma concentration.

It should be noted that the attending physician would know how to andwhen to terminate, interrupt, or adjust administration due to toxicityor organ dysfunctions. Conversely, the attending physician would alsoknow to adjust treatment to higher levels if the clinical response werenot adequate (precluding toxicity). The magnitude of an administrateddose in the management of the disorder of interest will vary with theseverity of the condition to be treated and to the route ofadministration. The severity of the condition may, for example, beevaluated, in part, by standard prognostic evaluation methods. Further,the dose and perhaps dose frequency, will also vary according to theage, body weight, and response of the individual patient. A programcomparable to that discussed above may be used in veterinary medicine.

Compounds disclosed herein can be evaluated for efficacy and toxicityusing known methods. For example, the toxicology of a particularcompound, or of a subset of the compounds, sharing certain chemicalmoieties, may be established by determining in vitro toxicity towards acell line, such as a mammalian, and preferably human, cell line. Theresults of such studies are often predictive of toxicity in animals,such as mammals, or more specifically, humans. Alternatively, thetoxicity of particular compounds in an animal model, such as mice, rats,rabbits, or monkeys, may be determined using known methods. The efficacyof a particular compound may be established using several recognizedmethods, such as in vitro methods, animal models, or human clinicaltrials. When selecting a model to determine efficacy, the skilledartisan can be guided by the state of the art to choose an appropriatemodel, dose, route of administration and/or regime.

Combination Therapies

In some embodiments, the compounds disclosed herein, such as a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition that includes a compound described herein, ora pharmaceutically acceptable salt thereof, can be used in combinationwith one or more additional agent(s). Examples of additional agents thatcan be used in combination with a compound of Formula (I), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes a compound of Formula (I), or apharmaceutically acceptable salt thereof, include, but are not limitedto, agents currently used in a conventional standard of care fortreating HCV, HCV protease inhibitors, HCV polymerase inhibitors, NS5Ainhibitors, other antiviral compounds, compounds of Formula (AA),(including pharmaceutically acceptable salts and pharmaceuticalcompositions that can include a compound of Formula (AA), or apharmaceutically acceptable salt thereof), compounds of Formula (BB)(including pharmaceutically acceptable salts and pharmaceuticalcompositions that can include a compound of Formula (BB), or apharmaceutically acceptable salt thereof), compounds of Formula (CC)(including pharmaceutically acceptable salts and pharmaceuticalcompositions that can include a compound of Formula (CC), or apharmaceutically acceptable salt thereof), and/or combinations thereof.In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used with one, two, three or more additional agents describedherein. A non-limiting list of examples of combinations of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition that includes a compound of Formula (I), or apharmaceutically acceptable salt thereof, is provided in Tables A, B, C,D and E.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used in combination with an agent(s) currently used in aconventional standard of care therapy. For example, for the treatment ofHCV, a compound disclosed herein can be used in combination withPegylated interferon-alpha-2a (brand name PEGASYS®) and ribavirin,Pegylated interferon-alpha-2b (brand name PEG-INTRON®) and ribavirin,Pegylated interferon-alpha-2a, Pegylated interferon-alpha-2b, orribavirin.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be substituted for an agent currently used in a conventionalstandard of care therapy. For example, for the treatment of HCV, acompound of Formula (I), or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition that includes a compound of Formula (I),or a pharmaceutically acceptable salt thereof, can be used in place ofribavirin.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used in combination with an interferon, such as a pegylatedinterferon. Examples of suitable interferons include, but are notlimited to, Pegylated interferon-alpha-2a (brand name PEGASYS®),Pegylated interferon-alpha-2b (brand name PEG-INTRON®), interferonalfacon-1 (brand name INFERGEN®), pegylated interferon lambda and/or acombination thereof.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used in combination with a HCV protease inhibitor. A non-limitinglist of example HCV protease inhibitors include the following: VX-950(TELAPREVIR®), MK-5172, ABT-450, BILN-2061, BI-201335, BMS-650032, SCH503034 (BOCEPREVIR®), GS-9256, GS-9451, IDX-320, ACH-1625, ACH-2684,TMC-435, ITMN-191 (DANOPREVIR®) and/or a combination thereof. AdditionalHCV protease inhibitors suitable for use in combination with a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition that includes a compound of Formula (I), or apharmaceutically acceptable salt thereof, include VP-19744, PSI-879,VCH-759/VX-759, HCV-371, IDX-375, GL-60667, JTK-109, PSI-6130, R1479,R-1626, R-7182, MK-0608, INX-8014, INX-8018, A-848837, A-837093,BILB-1941, VCH-916, VCH-716, GSK-71185, GSK-625433, XTL-2125 and thosedisclosed in PCT Publication No. WO 2012/142085, which is herebyincorporated by reference for the limited purpose of its disclosure ofHCV protease inhibitors, HCV polymerase inhibitors and NS5A inhibitors.A non-limiting list of example HCV protease inhibitors includes thecompounds numbered 1001-1016 in FIG. 1.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used in combination with a HCV polymerase inhibitor. In someembodiments, the HCV polymerase inhibitor can be a nucleoside inhibitor.In other embodiments, the HCV polymerase inhibitor can be anon-nucleoside inhibitor. Examples of suitable nucleoside inhibitorsinclude, but are not limited to, RG7128, PSI-7851, PSI-7977, INX-189,PSI-352938, PSI-661, 4′-azidouridine (including known prodrugs of4′-azidouridine), GS-6620, IDX-184, and TMC649128 and/or combinationsthereof. A non-limiting list of example nucleoside inhibitors includescompounds numbered 2001-2012 in FIG. 2. Examples of suitablenon-nucleoside inhibitors include, but are not limited to, ABT-333,ANA-598, VX-222, HCV-796, BI-207127, GS-9190, PF-00868554 (FILIBUVIR®),VX-497 and/or combinations thereof. A non-limiting list of examplenon-nucleoside inhibitors includes the compounds numbered 3001-3014 inFIG. 3. Further HCV polymerase inhibitors suitable for use incombination with a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,include VX-500, VX-813, VBY-376, TMC-435350, EZ-058, EZ-063, GS-9132,ACH-1095, IDX-136, IDX-316, ITMN-8356, ITMN-8347, ITMN-8096, ITMN-7587,VX-985, and those disclosed in PCT Publication No. WO 2012/142085.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used in combination with a NS5A inhibitor. Examples of NS5Ainhibitors include BMS-790052, PPI-461, ACH-2928, GS-5885, BMS-824393and/or combinations thereof. A non-limiting list of example NS5Ainhibitors includes the compounds numbered 4001-4012 in FIG. 4.Additional NS5A inhibitors suitable for use in combination with acompound of Formula (I), or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition that includes a compound of Formula (I),or a pharmaceutically acceptable salt thereof, include A-832, PPI-1301and those disclosed in PCT Publication No. WO 2012/142085.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used in combination with other antiviral compounds. Examples ofother antiviral compounds include, but are not limited to, Debio-025,MIR-122, cyclosporin A and/or combinations thereof. A non-limiting listof example other antiviral compounds includes the compounds numbered5001-5012 in FIG. 5.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used in combination with a compound of Formula (AA), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes a compound of Formula (AA), or apharmaceutically acceptable salt thereof (see, U.S. Publication No.2013/0164261, published Jun. 27, 2013, the contents of which areincorporated by reference in its entirety):

wherein: B^(AA1) can be an optionally substituted heterocyclic base oran optionally substituted heterocyclic base with a protected aminogroup; R^(AA1) can be selected from O⁻, OH, an optionally substitutedN-linked amino acid and an optionally substituted N-linked amino acidester derivative; R^(AA2) can be absent or selected from hydrogen, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted heterocyclyl and

wherein R^(AA6), R^(AA7) and R^(AA8) can be independently absent orhydrogen, and n^(AA) can be 0 or 1; provided that when R^(AAA) is O⁻ orOH, then R^(AA2) is absent, hydrogen or

R^(AA3) can be selected from hydrogen, halogen, —OR and —OC(═O)R^(AA10);R^(AA4) can be selected from halogen, —OR^(AA11) and —OC(═O)R^(AA12); orR^(AA3) and R^(AA4) can be both an oxygen atom which are linked togetherby a carbonyl group; R^(AA5) can be selected from an optionallysubstituted C₂₋₆ alkyl, an optionally substituted C₂₋₆ alkenyl, anoptionally substituted C₂₋₆ alkynyl and an optionally substituted C₃₋₆cycloalkyl; or R^(AAA) and R^(AA5) together can form —(C₁₋₆ alkyl)-O— or—O—(C₁₋₆ alkyl)-; R^(AA9) and R^(AA11) can be independently hydrogen oran optionally substituted C₁₋₆ alkyl; and R^(AA10) and R^(AA12) can beindependently an optionally substituted C₁₋₆ alkyl or an optionallysubstituted C₃₋₆ cycloalkyl. A non-limiting list of examples ofcompounds of Formula (AA) includes the compounds numbered 7000-7027 inFIG. 7.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used in combination with a compound of Formula (BB), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes a compound of Formula (BB), or apharmaceutically acceptable salt thereof (see, U.S. Publication No.2012/0165286, published Jun. 28, 2012, the contents of which areincorporated by reference in their entireties):

wherein B^(BB1) can be an optionally substituted heterocyclic base or anoptionally substituted heterocyclic base with a protected amino group;X^(BB) can be O (oxygen) or S (sulfur); R^(BB1) can be selected from—Z^(BB)—R^(BB9), an optionally substituted N-linked amino acid and anoptionally substituted N-linked amino acid ester derivative; Z^(BB) canbe selected from O (oxygen), S (sulfur) and N(R^(BB10))^(BB10); R^(BB2)and R^(BB3) can be independently selected from hydrogen, an optionallysubstituted C₁₋₆ alkyl, an optionally substituted C₂₋₆ alkenyl, anoptionally substituted C₂₋₆ alkynyl, an optionally substituted C₁₋₆haloalkyl and an optionally substituted aryl(C₁₋₆ alkyl); or R^(BB2) andR^(BB3) can be taken together to form a group selected from anoptionally substituted C₃₋₆ cycloalkyl, an optionally substituted C₃₋₆cycloalkenyl, an optionally substituted C₃₋₆ aryl and an optionallysubstituted C₃₋₆ heteroaryl; R^(BB4) can be selected from hydrogen,halogen, azido, cyano, an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₂₋₆ alkenyl, an optionally substituted C₂₋₆alkynyl and an optionally substituted allenyl; R^(BB5) can be hydrogenor an optionally substituted C₁₋₆ alkyl; R^(BB6) can be selected fromhydrogen, halogen, azido, amino, cyano, an optionally substituted C₁₋₆alkyl, —OR^(BB11) and —OC(═O)R^(BB12); R^(BB7) can be selected fromhydrogen, halogen, azido, cyano, an optionally substituted C₁₋₆ alkyl,—OR^(BB13) and —OC(═O)R^(BB14); R^(BB8) can be selected from hydrogen,halogen, azido, cyano, an optionally substituted C₁₋₆ alkyl, —OR^(BB15)and —OC(═O)R^(BB16); R^(BB9) can be selected from an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted heterocyclyl, anoptionally substituted aryl(C₁₋₆alkyl), an optionally substitutedheteroaryl(C₁₋₆alkyl) and an optionally substitutedheterocyclyl(C₁₋₆alkyl); R^(BB10) can be selected from hydrogen, anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substitutedheterocyclyl, an optionally substituted aryl(C₁₋₆alkyl), an optionallysubstituted heteroaryl(C₁₋₆alkyl) and an optionally substitutedheterocyclyl(C₁₋₆alkyl); R^(BB11), R^(BB13) and R^(BB15) can beindependently hydrogen or an optionally substituted C₁₋₆ alkyl; andR^(BB12), R^(BB14) and R^(BB16) can be independently an optionallysubstituted C₁₋₆ alkyl or an optionally substituted C₃₋₆ cycloalkyl. Insome embodiments, at least one of R^(BB2) and R^(BB3) is not hydrogen. Anon-limiting list of example compounds of Formula (BB) includes thecompound numbered 8000-8016 in FIG. 8.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be used in combination with a compound of Formula (CC), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes a compound of Formula (CC), or apharmaceutically acceptable salt thereof (see, U.S. Publication No.2012/0071434, published Mar. 22, 2012, the contents of which areincorporated by reference in its entirety):

wherein B^(CC1) can be an optionally substituted heterocyclic base or anoptionally substituted heterocyclic base with a protected amino group;R^(CC1) can be selected from O⁻, OH, an optionally substituted N-linkedamino acid and an optionally substituted N-linked amino acid esterderivative; R^(CC2) can be selected from an optionally substituted aryl,an optionally substituted heteroaryl, an optionally substitutedheterocyclyl and

wherein R^(CC19); R^(CC20) and R^(CC21) can be independently absent orhydrogen, and n^(CC) can be 0 or 1; provided that when R^(CC1) is O⁻ orOH, then R^(CC2) is

R^(CC3a) and R^(CC3b) can be independently selected from hydrogen,deuterium, an optionally substituted C₁₋₆ alkyl, an optionallysubstituted C₂₋₆ alkenyl, an optionally substituted C₂₋₆ alkynyl, anoptionally substituted C₁₋₆ haloalkyl and aryl(C₁₋₆ alkyl); or R^(CC3a)and R^(CC3b) can be taken together to form an optionally substitutedC₃₋₆ cycloalkyl; R^(CC4) can be selected from hydrogen, azido, anoptionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆alkenyl and an optionally substituted C₂₋₆ alkynyl; R^(CC5) can beselected from hydrogen, halogen, azido, cyano, an optionally substitutedC₁₋₆ alkyl, —OR^(CC10) and —OC(═O)R^(CC11); R^(CC6) can be selected fromhydrogen, halogen, azido, cyano, an optionally substituted C₁₋₆ alkyl,—OR^(CC12) and —OC(═O)R^(CC13); R^(CC7) can be selected from hydrogen,halogen, azido, cyano, an optionally substituted C₁₋₆ alkyl, —OR^(CC14)and —OC(═O)R^(CC15); or R^(CC6) and R^(CC7) can be both oxygen atoms andlinked together by a carbonyl group; R^(CC8) can be selected fromhydrogen, halogen, azido, cyano, an optionally substituted C₁₋₆ alkyl,—OR^(CC16) and —OC(═O)R^(CC17); R^(CC9) can be selected from hydrogen,azido, cyano, an optionally substituted C₁₋₆ alkyl and —OR^(CC18);R^(CC10); R^(CC12), R^(CC14); R^(CC16) and R^(CC18) can be independentlyselected from hydrogen and an optionally substituted C₁₋₆ alkyl; andR^(CC11); R^(CC13); R^(CC15) and R^(CC17) can be independently selectedfrom an optionally substituted C₁₋₆ alkyl and an optionally substitutedC₃₋₆ cycloalkyl. In some embodiments, when R^(CC3a); R^(CC3b); R^(CC4);R^(CC5); R^(CC7); R^(CC8) and R^(CC9) are all hydrogen, then R^(CC6) isnot azido. In some embodiments, R^(CC2) cannot be

when R^(CC3a) is hydrogen, R^(CC3b) is hydrogen, R^(CC4) is H, R^(CC5)is OH or H, R^(CC6) is hydrogen, OH, or —OC(═O)CH₃, R^(CC7) is hydrogen,OH, OCH₃ or —OC(═O)CH₃, R^(CC8) is hydrogen, OH or OCH₃, R^(CC9) is Hand B^(CC1) is an optionally substituted adenine, an optionallysubstituted guanine, an optionally substituted uracil or an optionallysubstituted hypoxanthine. In some embodiments, R^(CC2) cannot be

A non-limiting list of examples of compounds of Formula (CC) includesthe compounds numbered 6000-6078 in FIG. 6.

Some embodiments described herein relate to a method of ameliorating ortreating a HCV infection that can include contacting a cell infectedwith the HCV infection with an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, in combination withone or more agents selected from an interferon, ribavirin, a HCVprotease inhibitor, a HCV polymerase inhibitor, a NS5A inhibitor, anantiviral compound, a compound of Formula (AA), a compound of Formula(BB) and a compound of Formula (CC), or a pharmaceutically acceptablesalt of any of the aforementioned compounds.

Some embodiments described herein relate to a method of ameliorating ortreating a HCV infection that can include administering to a subjectsuffering from the HCV infection an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, incombination with one or more agents selected from an interferon,ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5Ainhibitor, an antiviral compound, a compound of Formula (AA), a compoundof Formula (BB) and a compound of Formula (CC), or a pharmaceuticallyacceptable salt of any of the aforementioned compounds.

Some embodiments described herein relate to a method of inhibiting thereplication of a hepatitis C virus that can include contacting a cellinfected with the hepatitis C virus with an effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,in combination with one or more agents selected from an interferon,ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5Ainhibitor, an antiviral compound, a compound of Formula (AA), a compoundof Formula (BB) and a compound of Formula (CC), or a pharmaceuticallyacceptable salt of any of the aforementioned compounds.

Some embodiments described herein relate to a method of inhibiting thereplication of a hepatitis C virus that can include administering to asubject infected with the hepatitis C virus an effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,in combination with one or more agents selected from an interferon,ribavirin, a HCV protease inhibitor, a HCV polymerase inhibitor, a NS5Ainhibitor, an antiviral compound, a compound of Formula (AA), a compoundof Formula (BB) and a compound of Formula (CC), or a pharmaceuticallyacceptable salt of any of the aforementioned compounds.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can be administered with one or more additionalagent(s) together in a single pharmaceutical composition. In someembodiments, a compound of Formula (I), or a pharmaceutically acceptablesalt the thereof, can be administered with one or more additionalagent(s) as two or more separate pharmaceutical compositions. Forexample, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, can be administered in one pharmaceutical composition, andat least one of the additional agents can be administered in a secondpharmaceutical composition. If there are at least two additional agents,one or more of the additional agents can be in a first pharmaceuticalcomposition that includes a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least one of the otheradditional agent(s) can be in a second pharmaceutical composition.

The dosing amount(s) and dosing schedule(s) when using a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition that includes a compound of Formula (I), or apharmaceutically acceptable salt thereof, and one or more additionalagents are within the knowledge of those skilled in the art. Forexample, when performing a conventional standard of care therapy usingart-recognized dosing amounts and dosing schedules, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition that includes a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be administered inaddition to that therapy, or in place of one of the agents of acombination therapy, using effective amounts and dosing protocols asdescribed herein.

The order of administration of a compound of Formula (I), or apharmaceutically acceptable salt thereof, with one or more additionalagent(s) can vary. In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be administered prior toall additional agents. In other embodiments, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, can be administered priorto at least one additional agent. In still other embodiments, a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, can beadministered concomitantly with one or more additional agent(s). In yetstill other embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be administered subsequentto the administration of at least one additional agent. In someembodiments, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, can be administered subsequent to the administration ofall additional agents.

In some embodiments, the combination of a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with one ormore additional agent(s) in FIGS. 1-8 (including pharmaceuticallyacceptable salts and prodrugs thereof) can result in an additive effect.In some embodiments, the combination of a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with one ormore additional agent(s) in FIGS. 1-8 (including pharmaceuticallyacceptable salts and prodrugs thereof) can result in a synergisticeffect. In some embodiments, the combination of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, in combination withone or more additional agent(s) in FIGS. 1-8 (including pharmaceuticallyacceptable salts and prodrugs thereof) can result in a stronglysynergistic effect. In some embodiments, the combination of a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, incombination with one or more additional agent(s) in FIGS. 1-8 (includingpharmaceutically acceptable salts and prodrugs thereof) is notantagonistic.

As used herein, the term “antagonistic” means that the activity of thecombination of compounds is less compared to the sum of the activitiesof the compounds in combination when the activity of each compound isdetermined individually (i.e. as a single compound). As used herein, theterm “synergistic effect” means that the activity of the combination ofcompounds is greater than the sum of the individual activities of thecompounds in the combination when the activity of each compound isdetermined individually. As used herein, the term “additive effect”means that the activity of the combination of compounds is about equalto the sum of the individual activities of the compound in thecombination when the activity of each compound is determinedindividually.

A potential advantage of utilizing a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with one ormore additional agent(s) in FIGS. 1-8 (including pharmaceuticallyacceptable salts thereof) may be a reduction in the required amount(s)of one or more compounds of FIGS. 1-8 (including pharmaceuticallyacceptable salts thereof) that is effective in treating a diseasecondition disclosed herein (for example, HCV), as compared to the amountrequired to achieve same therapeutic result when one or more compoundsof FIGS. 1-8 (including pharmaceutically acceptable salts thereof) areadministered without a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof. For example, the amount of a compound in FIGS.1-8 (including a pharmaceutically acceptable salt thereof), can be lesscompared to the amount of the compound in FIGS. 1-8 (including apharmaceutically acceptable salt thereof), needed to achieve the sameviral load reduction when administered as a monotherapy. Anotherpotential advantage of utilizing a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with one ormore additional agent(s) in FIGS. 1-8 (including pharmaceuticallyacceptable salts thereof) is that the use of two or more compoundshaving different mechanism of actions can create a higher barrier to thedevelopment of resistant viral strains compared to the barrier when acompound is administered as monotherapy.

Additional advantages of utilizing a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with one ormore additional agent(s) in FIGS. 1-8 (including pharmaceuticallyacceptable salts thereof) may include little to no cross resistancebetween a compound of Formula (I), or a pharmaceutically acceptable saltthereof, and one or more additional agent(s) in FIGS. 1-8 (includingpharmaceutically acceptable salts thereof) thereof; different routes forelimination of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and one or more additional agent(s) in FIGS.1-8 (including pharmaceutically acceptable salts thereof); little to nooverlapping toxicities between a compound of Formula (I), or apharmaceutically acceptable salt thereof, and one or more additionalagent(s) in FIGS. 1-8 (including pharmaceutically acceptable saltsthereof); little to no significant effects on cytochrome P450; little tono pharmacokinetic interactions between a compound of Formula (I), or apharmaceutically acceptable salt thereof, and one or more additionalagent(s) in FIGS. 1-8 (including pharmaceutically acceptable saltsthereof); greater percentage of subjects achieving a sustained viralresponse compared to when a compound is administered as monotherapyand/or a decrease in treatment time to achieve a sustained viralresponse compared to when a compound is administered as monotherapy.

A non-limiting list of example combination of compounds of Formula (I),or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes a compound described herein, with one or moreadditional agent(s) are provided in Tables A, B, C, D and E. Eachnumbered X and Y compound in Tables A, B, C, D and E has a correspondingname and/or structure provided in FIGS. 1-8. The numbered compounds inTables A, B, C, D and E includes pharmaceutically acceptable salts ofthe compounds and pharmaceutical compositions containing the compoundsor a pharmaceutically acceptable salt thereof. For example, 1001includes the compound corresponding to 1001, pharmaceutically acceptablesalts thereof, and pharmaceutical compositions that include compound1001 and/or a pharmaceutically acceptable salt thereof. The combinationsexemplified in Tables A, B, C, D and E are designated by the formulaX:Y, which represents a combination of a compound X with a compound Y.For example, the combination designated as 1001:9004 in Table Arepresents a combination of compound 1001 with compound 9004, includingpharmaceutically acceptable salts of compound 1001 and/or 9004, andpharmaceutical compositions including compound 1001 and 9004 (includingpharmaceutical compositions that include pharmaceutically acceptablesalts of compound 1001 and/or compound 9004). Thus, the combinationdesignated as 1001:9004 in Table A represents the combination ofTelaprevir (compound 1001, as shown in FIG. 1) and

(compound 9004, as shown in FIG. 9), including pharmaceuticallyacceptable salts of compound 1001 and/or 9004, and pharmaceuticalcompositions including compound 1001 and 9004 (including pharmaceuticalcompositions that include pharmaceutically acceptable salts of compound1001 and/or compound 9004). Each of the combinations provided in TablesA, B, C, D and E can be used with one, two, three or more additionalagents described herein. In some embodiments described herein, thecombination of agents can be used to treat, ameliorate and/or inhibit avirus and/or a viral infection, wherein the virus can be HCV and theviral infection can be an HCV viral infection.

TABLE A Example combinations of a compound X with a compound Y. X:Y X:YX:Y X:Y X:Y X:Y 1001:9000 1001:9001 1001:9002 1001:9003 1001:90041001:9005 1002:9000 1002:9001 1002:9002 1002:9003 1002:9004 1002:90051003:9000 1003:9001 1003:9002 1003:9003 1003:9004 1003:9005 1004:90001004:9001 1004:9002 1004:9003 1004:9004 1004:9005 1005:9000 1005:90011005:9002 1005:9003 1005:9004 1005:9005 1006:9000 1006:9001 1006:90021006:9003 1006:9004 1006:9005 1007:9000 1007:9001 1007:9002 1007:90031007:9004 1007:9005 1008:9000 1008:9001 1008:9002 1008:9003 1008:90041008:9005 1009:9000 1009:9001 1009:9002 1009:9003 1009:9004 1009:90051010:9000 1010:9001 1010:9002 1010:9003 1010:9004 1010:9005 1011:90001011:9001 1011:9002 1011:9003 1011:9004 1011:9005 1012:9000 1012:90011012:9002 1012:9003 1012:9004 1012:9005 1013:9000 1013:9001 1013:90021013:9003 1013:9004 1013:9005 1014:9000 1014:9001 1014:9002 1014:90031014:9004 1014:9005 1015:9000 1015:9001 1015:9002 1015:9003 1015:90041015:9005 1016:9000 1016:9001 1016:9002 1016:9003 1016:9004 1016:90052001:9000 2001:9001 2001:9002 2001:9003 2001:9004 2001:9005 2002:90002002:9001 2002:9002 2002:9003 2002:9004 2002:9005 2003:9000 2003:90012003:9002 2003:9003 2003:9004 2003:9005 2004:9000 2004:9001 2004:90022004:9003 2004:9004 2004:9005 2005:9000 2005:9001 2005:9002 2005:90032005:9004 2005:9005 2006:9000 2006:9001 2006:9002 2006:9003 2006:90042006:9005 2007:9000 2007:9001 2007:9002 2007:9003 2007:9004 2007:90052008:9000 2008:9001 2008:9002 2008:9003 2008:9004 2008:9005 2009:90002009:9001 2009:9002 2009:9003 2009:9004 2009:9005 2010:9000 2010:90012010:9002 2010:9003 2010:9004 2010:9005 2011:9000 2011:9001 2011:90022011:9003 2011:9004 2011:9005 2012:9000 2012:9001 2012:9002 2012:90032012:9004 2012:9005 1001:9006 1001:9007 1001:9008 1001:9009 1001:90101001:9011 1002:9006 1002:9007 1002:9008 1002:9009 1002:9010 1002:90111003:9006 1003:9007 1003:9008 1003:9009 1003:9010 1003:9011 1004:90061004:9007 1004:9008 1004:9009 1004:9010 1004:9011 1005:9006 1005:90071005:9008 1005:9009 1005:9010 1005:9011 1006:9006 1006:9007 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2012:9071 1001:9072 1001:9073 1001:9074 1001:9075 1001:90761001:9077 1002:9072 1002:9073 1002:9074 1002:9075 1002:9076 1002:90771003:9072 1003:9073 1003:9074 1003:9075 1003:9076 1003:9077 1004:90721004:9073 1004:9074 1004:9075 1004:9076 1004:9077 1005:9072 1005:90731005:9074 1005:9075 1005:9076 1005:9077 1006:9072 1006:9073 1006:90741006:9075 1006:9076 1006:9077 1007:9072 1007:9073 1007:9074 1007:90751007:9076 1007:9077 1008:9072 1008:9073 1008:9074 1008:9075 1008:90761008:9077 1009:9072 1009:9073 1009:9074 1009:9075 1009:9076 1009:90771010:9072 1010:9073 1010:9074 1010:9075 1010:9076 1010:9077 1011:90721011:9073 1011:9074 1011:9075 1011:9076 1011:9077 1012:9072 1012:90731012:9074 1012:9075 1012:9076 1012:9077 1013:9072 1013:9073 1013:90741013:9075 1013:9076 1013:9077 1014:9072 1014:9073 1014:9074 1014:90751014:9076 1014:9077 1015:9072 1015:9073 1015:9074 1015:9075 1015:90761015:9077 1016:9072 1016:9073 1016:9074 1016:9075 1016:9076 1016:90772001:9072 2001:9073 2001:9074 2001:9075 2001:9076 2001:9077 2002:90722002:9073 2002:9074 2002:9075 2002:9076 2002:9077 2003:9072 2003:90732003:9074 2003:9075 2003:9076 2003:9077 2004:9072 2004:9073 2004:90742004:9075 2004:9076 2004:9077 2005:9072 2005:9073 2005:9074 2005:90752005:9076 2005:9077 2006:9072 2006:9073 2006:9074 2006:9075 2006:90762006:9077 2007:9072 2007:9073 2007:9074 2007:9075 2007:9076 2007:90772008:9072 2008:9073 2008:9074 2008:9075 2008:9076 2008:9077 2009:90722009:9073 2009:9074 2009:9075 2009:9076 2009:9077 2010:9072 2010:90732010:9074 2010:9075 2010:9076 2010:9077 2011:9072 2011:9073 2011:90742011:9075 2011:9076 2011:9077 2012:9072 2012:9073 2012:9074 2012:90752012:9076 2012:9077 1001:9078 1001:9079 1001:9080 1001:9081 1001:90821001:9083 1002:9078 1002:9079 1002:9080 1002:9081 1002:9082 1002:90831003:9078 1003:9079 1003:9080 1003:9081 1003:9082 1003:9083 1004:90781004:9079 1004:9080 1004:9081 1004:9082 1004:9083 1005:9078 1005:90791005:9080 1005:9081 1005:9082 1005:9083 1006:9078 1006:9079 1006:90801006:9081 1006:9082 1006:9083 1007:9078 1007:9079 1007:9080 1007:90811007:9082 1007:9083 1008:9078 1008:9079 1008:9080 1008:9081 1008:90821008:9083 1009:9078 1009:9079 1009:9080 1009:9081 1009:9082 1009:90831010:9078 1010:9079 1010:9080 1010:9081 1010:9082 1010:9083 1011:90781011:9079 1011:9080 1011:9081 1011:9082 1011:9083 1012:9078 1012:90791012:9080 1012:9081 1012:9082 1012:9083 1013:9078 1013:9079 1013:90801013:9081 1013:9082 1013:9083 1014:9078 1014:9079 1014:9080 1014:90811014:9082 1014:9083 1015:9078 1015:9079 1015:9080 1015:9081 1015:90821015:9083 1016:9078 1016:9079 1016:9080 1016:9081 1016:9082 1016:90832001:9078 2001:9079 2001:9080 2001:9081 2001:9082 2001:9083 2002:90782002:9079 2002:9080 2002:9081 2002:9082 2002:9083 2003:9078 2003:90792003:9080 2003:9081 2003:9082 2003:9083 2004:9078 2004:9079 2004:90802004:9081 2004:9082 2004:9083 2005:9078 2005:9079 2005:9080 2005:90812005:9082 2005:9083 2006:9078 2006:9079 2006:9080 2006:9081 2006:90822006:9083 2007:9078 2007:9079 2007:9080 2007:9081 2007:9082 2007:90832008:9078 2008:9079 2008:9080 2008:9081 2008:9082 2008:9083 2009:90782009:9079 2009:9080 2009:9081 2009:9082 2009:9083 2010:9078 2010:90792010:9080 2010:9081 2010:9082 2010:9083 2011:9078 2011:9079 2011:90802011:9081 2011:9082 2011:9083 2012:9078 2012:9079 2012:9080 2012:90812012:9082 2012:9083 1001:9084 1001:9085 1001:9086 1001:9087 1001:90881001:9089 1002:9084 1002:9085 1002:9086 1002:9087 1002:9088 1002:90891003:9084 1003:9085 1003:9086 1003:9087 1003:9088 1003:9089 1004:90841004:9085 1004:9086 1004:9087 1004:9088 1004:9089 1005:9084 1005:90851005:9086 1005:9087 1005:9088 1005:9089 1006:9084 1006:9085 1006:90861006:9087 1006:9088 1006:9089 1007:9084 1007:9085 1007:9086 1007:90871007:9088 1007:9089 1008:9084 1008:9085 1008:9086 1008:9087 1008:90881008:9089 1009:9084 1009:9085 1009:9086 1009:9087 1009:9088 1009:90891010:9084 1010:9085 1010:9086 1010:9087 1010:9088 1010:9089 1011:90841011:9085 1011:9086 1011:9087 1011:9088 1011:9089 1012:9084 1012:90851012:9086 1012:9087 1012:9088 1012:9089 1013:9084 1013:9085 1013:90861013:9087 1013:9088 1013:9089 1014:9084 1014:9085 1014:9086 1014:90871014:9088 1014:9089 1015:9084 1015:9085 1015:9086 1015:9087 1015:90881015:9089 1016:9084 1016:9085 1016:9086 1016:9087 1016:9088 1016:90892001:9084 2001:9085 2001:9086 2001:9087 2001:9088 2001:9089 2002:90842002:9085 2002:9086 2002:9087 2002:9088 2002:9089 2003:9084 2003:90852003:9086 2003:9087 2003:9088 2003:9089 2004:9084 2004:9085 2004:90862004:9087 2004:9088 2004:9089 2005:9084 2005:9085 2005:9086 2005:90872005:9088 2005:9089 2006:9084 2006:9085 2006:9086 2006:9087 2006:90882006:9089 2007:9084 2007:9085 2007:9086 2007:9087 2007:9088 2007:90892008:9084 2008:9085 2008:9086 2008:9087 2008:9088 2008:9089 2009:90842009:9085 2009:9086 2009:9087 2009:9088 2009:9089 2010:9084 2010:90852010:9086 2010:9087 2010:9088 2010:9089 2011:9084 2011:9085 2011:90862011:9087 2011:9088 2011:9089 2012:9084 2012:9085 2012:9086 2012:90872012:9088 2012:9089 1001:9090 1001:9091 1001:9092 1001:9093 1001:90941001:9095 1002:9090 1002:9091 1002:9092 1002:9093 1002:9094 1002:90951003:9090 1003:9091 1003:9092 1003:9093 1003:9094 1003:9095 1004:90901004:9091 1004:9092 1004:9093 1004:9094 1004:9095 1005:9090 1005:90911005:9092 1005:9093 1005:9094 1005:9095 1006:9090 1006:9091 1006:90921006:9093 1006:9094 1006:9095 1007:9090 1007:9091 1007:9092 1007:90931007:9094 1007:9095 1008:9090 1008:9091 1008:9092 1008:9093 1008:90941008:9095 1009:9090 1009:9091 1009:9092 1009:9093 1009:9094 1009:90951010:9090 1010:9091 1010:9092 1010:9093 1010:9094 1010:9095 1011:90901011:9091 1011:9092 1011:9093 1011:9094 1011:9095 1012:9090 1012:90911012:9092 1012:9093 1012:9094 1012:9095 1013:9090 1013:9091 1013:90921013:9093 1013:9094 1013:9095 1014:9090 1014:9091 1014:9092 1014:90931014:9094 1014:9095 1015:9090 1015:9091 1015:9092 1015:9093 1015:90941015:9095 1016:9090 1016:9091 1016:9092 1016:9093 1016:9094 1016:90952001:9090 2001:9091 2001:9092 2001:9093 2001:9094 2001:9095 2002:90902002:9091 2002:9092 2002:9093 2002:9094 2002:9095 2003:9090 2003:90912003:9092 2003:9093 2003:9094 2003:9095 2004:9090 2004:9091 2004:90922004:9093 2004:9094 2004:9095 2005:9090 2005:9091 2005:9092 2005:90932005:9094 2005:9095 2006:9090 2006:9091 2006:9092 2006:9093 2006:90942006:9095 2007:9090 2007:9091 2007:9092 2007:9093 2007:9094 2007:90952008:9090 2008:9091 2008:9092 2008:9093 2008:9094 2008:9095 2009:90902009:9091 2009:9092 2009:9093 2009:9094 2009:9095 2010:9090 2010:90912010:9092 2010:9093 2010:9094 2010:9095 2011:9090 2011:9091 2011:90922011:9093 2011:9094 2011:9095 2012:9090 2012:9091 2012:9092 2012:90932012:9094 2012:9095 1001:9096 1001:9097 1001:9098 1001:9099 1001:91001001:9101 1002:9096 1002:9097 1002:9098 1002:9099 1002:9100 1002:91011003:9096 1003:9097 1003:9098 1003:9099 1003:9100 1003:9101 1004:90961004:9097 1004:9098 1004:9099 1004:9100 1004:9101 1005:9096 1005:90971005:9098 1005:9099 1005:9100 1005:9101 1006:9096 1006:9097 1006:90981006:9099 1006:9100 1006:9101 1007:9096 1007:9097 1007:9098 1007:90991007:9100 1007:9101 1008:9096 1008:9097 1008:9098 1008:9099 1008:91001008:9101 1009:9096 1009:9097 1009:9098 1009:9099 1009:9100 1009:91011010:9096 1010:9097 1010:9098 1010:9099 1010:9100 1010:9101 1011:90961011:9097 1011:9098 1011:9099 1011:9100 1011:9101 1012:9096 1012:90971012:9098 1012:9099 1012:9100 1012:9101 1013:9096 1013:9097 1013:90981013:9099 1013:9100 1013:9101 1014:9096 1014:9097 1014:9098 1014:90991014:9100 1014:9101 1015:9096 1015:9097 1015:9098 1015:9099 1015:91001015:9101 1016:9096 1016:9097 1016:9098 1016:9099 1016:9100 1016:91012001:9096 2001:9097 2001:9098 2001:9099 2001:9100 2001:9101 2002:90962002:9097 2002:9098 2002:9099 2002:9100 2002:9101 2003:9096 2003:90972003:9098 2003:9099 2003:9100 2003:9101 2004:9096 2004:9097 2004:90982004:9099 2004:9100 2004:9101 2005:9096 2005:9097 2005:9098 2005:90992005:9100 2005:9101 2006:9096 2006:9097 2006:9098 2006:9099 2006:91002006:9101 2007:9096 2007:9097 2007:9098 2007:9099 2007:9100 2007:91012008:9096 2008:9097 2008:9098 2008:9099 2008:9100 2008:9101 2009:90962009:9097 2009:9098 2009:9099 2009:9100 2009:9101 2010:9096 2010:90972010:9098 2010:9099 2010:9100 2010:9101 2011:9096 2011:9097 2011:90982011:9099 2011:9100 2011:9101 2012:9096 2012:9097 2012:9098 2012:90992012:9100 2012:9101 1001:9102 1001:9103 1001:9104 1001:9105 — —1002:9102 1002:9103 1002:9104 1002:9105 1003:9102 1003:9103 1003:91041003:9105 1004:9102 1004:9103 1004:9104 1004:9105 1005:9102 1005:91031005:9104 1005:9105 1006:9102 1006:9103 1006:9104 1006:9105 1007:91021007:9103 1007:9104 1007:9105 1008:9102 1008:9103 1008:9104 1008:91051009:9102 1009:9103 1009:9104 1009:9105 1010:9102 1010:9103 1010:91041010:9105 1011:9102 1011:9103 1011:9104 1011:9105 1012:9102 1012:91031012:9104 1012:9105 1013:9102 1013:9103 1013:9104 1013:9105 1014:91021014:9103 1014:9104 1014:9105 1015:9102 1015:9103 1015:9104 1015:91051016:9102 1016:9103 1016:9104 1016:9105 2001:9102 2001:9103 2001:91042001:9105 2002:9102 2002:9103 2002:9104 2002:9105 2003:9102 2003:91032003:9104 2003:9105 2004:9102 2004:9103 2004:9104 2004:9105 2005:91022005:9103 2005:9104 2005:9105 2006:9102 2006:9103 2006:9104 2006:91052007:9102 2007:9103 2007:9104 2007:9105 2008:9102 2008:9103 2008:91042008:9105 2009:9102 2009:9103 2009:9104 2009:9105 2010:9102 2010:91032010:9104 2010:9105 2011:9102 2011:9103 2011:9104 2011:9105 2012:91022012:9103 2012:9104 2012:9105

TABLE B Example combinations of a compound X with a compound Y. X:Y X:YX:Y X:Y X:Y X:Y 3001:9000 3001:9001 3001:9002 3001:9003 3001:90043001:9005 3002:9000 3002:9001 3002:9002 3002:9003 3002:9004 3002:90053003:9000 3003:9001 3003:9002 3003:9003 3003:9004 3003:9005 3004:90003004:9001 3004:9002 3004:9003 3004:9004 3004:9005 3005:9000 3005:90013005:9002 3005:9003 3005:9004 3005:9005 3006:9000 3006:9001 3006:90023006:9003 3006:9004 3006:9005 3007:9000 3007:9001 3007:9002 3007:90033007:9004 3007:9005 3008:9000 3008:9001 3008:9002 3008:9003 3008:90043008:9005 3009:9000 3009:9001 3009:9002 3009:9003 3009:9004 3009:90053010:9000 3010:9001 3010:9002 3010:9003 3010:9004 3010:9005 3011:90003011:9001 3011:9002 3011:9003 3011:9004 3011:9005 3012:9000 3012:90013012:9002 3012:9003 3012:9004 3012:9005 3013:9000 3013:9001 3013:90023013:9003 3013:9004 3013:9005 3014:9000 3014:9001 3014:9002 3014:90033014:9004 3014:9005 4001:9000 4001:9001 4001:9002 4001:9003 4001:90044001:9005 4002:9000 4002:9001 4002:9002 4002:9003 4002:9004 4002:90054003:9000 4003:9001 4003:9002 4003:9003 4003:9004 4003:9005 4004:90004004:9001 4004:9002 4004:9003 4004:9004 4004:9005 4005:9000 4005:90014005:9002 4005:9003 4005:9004 4005:9005 4006:9000 4006:9001 4006:90024006:9003 4006:9004 4006:9005 4007:9000 4007:9001 4007:9002 4007:90034007:9004 4007:9005 4008:9000 4008:9001 4008:9002 4008:9003 4008:90044008:9005 4009:9000 4009:9001 4009:9002 4009:9003 4009:9004 4009:90054010:9000 4010:9001 4010:9002 4010:9003 4010:9004 4010:9005 4011:90004011:9001 4011:9002 4011:9003 4011:9004 4011:9005 4012:9000 4012:90014012:9002 4012:9003 4012:9004 4012:9005 5001:9000 5001:9001 5001:90025001:9003 5001:9004 5001:9005 5002:9000 5002:9001 5002:9002 5002:90035002:9004 5002:9005 5003:9000 5003:9001 5003:9002 5003:9003 5003:90045003:9005 5004:9000 5004:9001 5004:9002 5004:9003 5004:9004 5004:90055005:9000 5005:9001 5005:9002 5005:9003 5005:9004 5005:9005 5006:90005006:9001 5006:9002 5006:9003 5006:9004 5006:9005 5007:9000 5007:90015007:9002 5007:9003 5007:9004 5007:9005 5008:9000 5008:9001 5008:90025008:9003 5008:9004 5008:9005 5009:9000 5009:9001 5009:9002 5009:90035009:9004 5009:9005 5010:9000 5010:9001 5010:9002 5010:9003 5010:90045010:9005 5011:9000 5011:9001 5011:9002 5011:9003 5011:9004 5011:90055012:9000 5012:9001 5012:9002 5012:9003 5012:9004 5012:9005 3001:90063001:9007 3001:9008 3001:9009 3001:9010 3001:9011 3002:9006 3002:90073002:9008 3002:9009 3002:9010 3002:9011 3003:9006 3003:9007 3003:90083003:9009 3003:9010 3003:9011 3004:9006 3004:9007 3004:9008 3004:90093004:9010 3004:9011 3005:9006 3005:9007 3005:9008 3005:9009 3005:90103005:9011 3006:9006 3006:9007 3006:9008 3006:9009 3006:9010 3006:90113007:9006 3007:9007 3007:9008 3007:9009 3007:9010 3007:9011 3008:90063008:9007 3008:9008 3008:9009 3008:9010 3008:9011 3009:9006 3009:90073009:9008 3009:9009 3009:9010 3009:9011 3010:9006 3010:9007 3010:90083010:9009 3010:9010 3010:9011 3011:9006 3011:9007 3011:9008 3011:90093011:9010 3011:9011 3012:9006 3012:9007 3012:9008 3012:9009 3012:90103012:9011 3013:9006 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4009:9085 4009:9086 4009:9087 4009:9088 4009:90894010:9084 4010:9085 4010:9086 4010:9087 4010:9088 4010:9089 4011:90844011:9085 4011:9086 4011:9087 4011:9088 4011:9089 4012:9084 4012:90854012:9086 4012:9087 4012:9088 4012:9089 5001:9084 5001:9085 5001:90865001:9087 5001:9088 5001:9089 5002:9084 5002:9085 5002:9086 5002:90875002:9088 5002:9089 5003:9084 5003:9085 5003:9086 5003:9087 5003:90885003:9089 5004:9084 5004:9085 5004:9086 5004:9087 5004:9088 5004:90895005:9084 5005:9085 5005:9086 5005:9087 5005:9088 5005:9089 5006:90845006:9085 5006:9086 5006:9087 5006:9088 5006:9089 5007:9084 5007:90855007:9086 5007:9087 5007:9088 5007:9089 5008:9084 5008:9085 5008:90865008:9087 5008:9088 5008:9089 5009:9084 5009:9085 5009:9086 5009:90875009:9088 5009:9089 5010:9084 5010:9085 5010:9086 5010:9087 5010:90885010:9089 5011:9084 5011:9085 5011:9086 5011:9087 5011:9088 5011:90895012:9084 5012:9085 5012:9086 5012:9087 5012:9088 5012:9089 3001:90903001:9091 3001:9092 3001:9093 3001:9094 3001:9095 3002:9090 3002:90913002:9092 3002:9093 3002:9094 3002:9095 3003:9090 3003:9091 3003:90923003:9093 3003:9094 3003:9095 3004:9090 3004:9091 3004:9092 3004:90933004:9094 3004:9095 3005:9090 3005:9091 3005:9092 3005:9093 3005:90943005:9095 3006:9090 3006:9091 3006:9092 3006:9093 3006:9094 3006:90953007:9090 3007:9091 3007:9092 3007:9093 3007:9094 3007:9095 3008:90903008:9091 3008:9092 3008:9093 3008:9094 3008:9095 3009:9090 3009:90913009:9092 3009:9093 3009:9094 3009:9095 3010:9090 3010:9091 3010:90923010:9093 3010:9094 3010:9095 3011:9090 3011:9091 3011:9092 3011:90933011:9094 3011:9095 3012:9090 3012:9091 3012:9092 3012:9093 3012:90943012:9095 3013:9090 3013:9091 3013:9092 3013:9093 3013:9094 3013:90953014:9090 3014:9091 3014:9092 3014:9093 3014:9094 3014:9095 4001:90904001:9091 4001:9092 4001:9093 4001:9094 4001:9095 4002:9090 4002:90914002:9092 4002:9093 4002:9094 4002:9095 4003:9090 4003:9091 4003:90924003:9093 4003:9094 4003:9095 4004:9090 4004:9091 4004:9092 4004:90934004:9094 4004:9095 4005:9090 4005:9091 4005:9092 4005:9093 4005:90944005:9095 4006:9090 4006:9091 4006:9092 4006:9093 4006:9094 4006:90954007:9090 4007:9091 4007:9092 4007:9093 4007:9094 4007:9095 4008:90904008:9091 4008:9092 4008:9093 4008:9094 4008:9095 4009:9090 4009:90914009:9092 4009:9093 4009:9094 4009:9095 4010:9090 4010:9091 4010:90924010:9093 4010:9094 4010:9095 4011:9090 4011:9091 4011:9092 4011:90934011:9094 4011:9095 4012:9090 4012:9091 4012:9092 4012:9093 4012:90944012:9095 5001:9090 5001:9091 5001:9092 5001:9093 5001:9094 5001:90955002:9090 5002:9091 5002:9092 5002:9093 5002:9094 5002:9095 5003:90905003:9091 5003:9092 5003:9093 5003:9094 5003:9095 5004:9090 5004:90915004:9092 5004:9093 5004:9094 5004:9095 5005:9090 5005:9091 5005:90925005:9093 5005:9094 5005:9095 5006:9090 5006:9091 5006:9092 5006:90935006:9094 5006:9095 5007:9090 5007:9091 5007:9092 5007:9093 5007:90945007:9095 5008:9090 5008:9091 5008:9092 5008:9093 5008:9094 5008:90955009:9090 5009:9091 5009:9092 5009:9093 5009:9094 5009:9095 5010:90905010:9091 5010:9092 5010:9093 5010:9094 5010:9095 5011:9090 5011:90915011:9092 5011:9093 5011:9094 5011:9095 5012:9090 5012:9091 5012:90925012:9093 5012:9094 5012:9095 3001:9096 3001:9097 3001:9098 3001:90993001:9100 3001:9101 3002:9096 3002:9097 3002:9098 3002:9099 3002:91003002:9101 3003:9096 3003:9097 3003:9098 3003:9099 3003:9100 3003:91013004:9096 3004:9097 3004:9098 3004:9099 3004:9100 3004:9101 3005:90963005:9097 3005:9098 3005:9099 3005:9100 3005:9101 3006:9096 3006:90973006:9098 3006:9099 3006:9100 3006:9101 3007:9096 3007:9097 3007:90983007:9099 3007:9100 3007:9101 3008:9096 3008:9097 3008:9098 3008:90993008:9100 3008:9101 3009:9096 3009:9097 3009:9098 3009:9099 3009:91003009:9101 3010:9096 3010:9097 3010:9098 3010:9099 3010:9100 3010:91013011:9096 3011:9097 3011:9098 3011:9099 3011:9100 3011:9101 3012:90963012:9097 3012:9098 3012:9099 3012:9100 3012:9101 3013:9096 3013:90973013:9098 3013:9099 3013:9100 3013:9101 3014:9096 3014:9097 3014:90983014:9099 3014:9100 3014:9101 4001:9096 4001:9097 4001:9098 4001:90994001:9100 4001:9101 4002:9096 4002:9097 4002:9098 4002:9099 4002:91004002:9101 4003:9096 4003:9097 4003:9098 4003:9099 4003:9100 4003:91014004:9096 4004:9097 4004:9098 4004:9099 4004:9100 4004:9101 4005:90964005:9097 4005:9098 4005:9099 4005:9100 4005:9101 4006:9096 4006:90974006:9098 4006:9099 4006:9100 4006:9101 4007:9096 4007:9097 4007:90984007:9099 4007:9100 4007:9101 4008:9096 4008:9097 4008:9098 4008:90994008:9100 4008:9101 4009:9096 4009:9097 4009:9098 4009:9099 4009:91004009:9101 4010:9096 4010:9097 4010:9098 4010:9099 4010:9100 4010:91014011:9096 4011:9097 4011:9098 4011:9099 4011:9100 4011:9101 4012:90964012:9097 4012:9098 4012:9099 4012:9100 4012:9101 5001:9096 5001:90975001:9098 5001:9099 5001:9100 5001:9101 5002:9096 5002:9097 5002:90985002:9099 5002:9100 5002:9101 5003:9096 5003:9097 5003:9098 5003:90995003:9100 5003:9101 5004:9096 5004:9097 5004:9098 5004:9099 5004:91005004:9101 5005:9096 5005:9097 5005:9098 5005:9099 5005:9100 5005:91015006:9096 5006:9097 5006:9098 5006:9099 5006:9100 5006:9101 5007:90965007:9097 5007:9098 5007:9099 5007:9100 5007:9101 5008:9096 5008:90975008:9098 5008:9099 5008:9100 5008:9101 5009:9096 5009:9097 5009:90985009:9099 5009:9100 5009:9101 5010:9096 5010:9097 5010:9098 5010:90995010:9100 5010:9101 5011:9096 5011:9097 5011:9098 5011:9099 5011:91005011:9101 5012:9096 5012:9097 5012:9098 5012:9099 5012:9100 5012:91013001:9102 3001:9103 3001:9104 3001:9105 — — 3002:9102 3002:91033002:9104 3002:9105 3003:9102 3003:9103 3003:9104 3003:9105 3004:91023004:9103 3004:9104 3004:9105 3005:9102 3005:9103 3005:9104 3005:91053006:9102 3006:9103 3006:9104 3006:9105 3007:9102 3007:9103 3007:91043007:9105 3008:9102 3008:9103 3008:9104 3008:9105 3009:9102 3009:91033009:9104 3009:9105 3010:9102 3010:9103 3010:9104 3010:9105 3011:91023011:9103 3011:9104 3011:9105 3012:9102 3012:9103 3012:9104 3012:91053013:9102 3013:9103 3013:9104 3013:9105 3014:9102 3014:9103 3014:91043014:9105 4001:9102 4001:9103 4001:9104 4001:9105 4002:9102 4002:91034002:9104 4002:9105 4003:9102 4003:9103 4003:9104 4003:9105 4004:91024004:9103 4004:9104 4004:9105 4005:9102 4005:9103 4005:9104 4005:91054006:9102 4006:9103 4006:9104 4006:9105 4007:9102 4007:9103 4007:91044007:9105 4008:9102 4008:9103 4008:9104 4008:9105 4009:9102 4009:91034009:9104 4009:9105 4010:9102 4010:9103 4010:9104 4010:9105 4011:91024011:9103 4011:9104 4011:9105 4012:9102 4012:9103 4012:9104 4012:91055001:9102 5001:9103 5001:9104 5001:9105 5002:9102 5002:9103 5002:91045002:9105 5003:9102 5003:9103 5003:9104 5003:9105 5004:9102 5004:91035004:9104 5004:9105 5005:9102 5005:9103 5005:9104 5005:9105 5006:91025006:9103 5006:9104 5006:9105 5007:9102 5007:9103 5007:9104 5007:91055008:9102 5008:9103 5008:9104 5008:9105 5009:9102 5009:9103 5009:91045009:9105 5010:9102 5010:9103 5010:9104 5010:9105 5011:9102 5011:91035011:9104 5011:9105 5012:9102 5012:9103 5012:9104 5012:9105

TABLE C Example combinations of a compound X with a compound Y. X:Y X:YX:Y X:Y X:Y X:Y 9000:7000 9001:7000 9002:7000 9003:7000 9004:70009005:7000 9000:7001 9001:7001 9002:7001 9003:7001 9004:7001 9005:70019000:7002 9001:7002 9002:7002 9003:7002 9004:7002 9005:7002 9000:70039001:7003 9002:7003 9003:7003 9004:7003 9005:7003 9000:7004 9001:70049002:7004 9003:7004 9004:7004 9005:7004 9000:7005 9001:7005 9002:70059003:7005 9004:7005 9005:7005 9000:7006 9001:7006 9002:7006 9003:70069004:7006 9005:7006 9000:7007 9001:7007 9002:7007 9003:7007 9004:70079005:7007 9000:7008 9001:7008 9002:7008 9003:7008 9004:7008 9005:70089000:7009 9001:7009 9002:7009 9003:7009 9004:7009 9005:7009 9000:70109001:7010 9002:7010 9003:7010 9004:7010 9005:7010 9000:7011 9001:70119002:7011 9003:7011 9004:7011 9005:7011 9000:7012 9001:7012 9002:70129003:7012 9004:7012 9005:7012 9000:7013 9001:7013 9002:7013 9003:70139004:7013 9005:7013 9000:7014 9001:7014 9002:7014 9003:7014 9004:70149005:7014 9000:7015 9001:7015 9002:7015 9003:7015 9004:7015 9005:70159000:7016 9001:7016 9002:7016 9003:7016 9004:7016 9005:7016 9000:70179001:7017 9002:7017 9003:7017 9004:7017 9005:7017 9000:7018 9001:70189002:7018 9003:7018 9004:7018 9005:7018 9000:7019 9001:7019 9002:70199003:7019 9004:7019 9005:7019 9000:7020 9001:7020 9002:7020 9003:70209004:7020 9005:7020 9000:7021 9001:7021 9002:7021 9003:7021 9004:70219005:7021 9000:7022 9001:7022 9002:7022 9003:7022 9004:7022 9005:70229000:7023 9001:7023 9002:7023 9003:7023 9004:7023 9005:7023 9000:70249001:7024 9002:7024 9003:7024 9004:7024 9005:7024 9000:7025 9001:70259002:7025 9003:7025 9004:7025 9005:7025 9000:7026 9001:7026 9002:70269003:7026 9004:7026 9005:7026 9000:7027 9001:7027 9002:7027 9003:70279004:7027 9005:7027 9006:7000 9007:7000 9008:7000 9009:7000 9010:70009011:7000 9006:7001 9007:7001 9008:7001 9009:7001 9010:7001 9011:70019006:7002 9007:7002 9008:7002 9009:7002 9010:7002 9011:7002 9006:70039007:7003 9008:7003 9009:7003 9010:7003 9011:7003 9006:7004 9007:70049008:7004 9009:7004 9010:7004 9011:7004 9006:7005 9007:7005 9008:70059009:7005 9010:7005 9011:7005 9006:7006 9007:7006 9008:7006 9009:70069010:7006 9011:7006 9006:7007 9007:7007 9008:7007 9009:7007 9010:70079011:7007 9006:7008 9007:7008 9008:7008 9009:7008 9010:7008 9011:70089006:7009 9007:7009 9008:7009 9009:7009 9010:7009 9011:7009 9006:70109007:7010 9008:7010 9009:7010 9010:7010 9011:7010 9006:7011 9007:70119008:7011 9009:7011 9010:7011 9011:7011 9006:7012 9007:7012 9008:70129009:7012 9010:7012 9011:7012 9006:7013 9007:7013 9008:7013 9009:70139010:7013 9011:7013 9006:7014 9007:7014 9008:7014 9009:7014 9010:70149011:7014 9006:7015 9007:7015 9008:7015 9009:7015 9010:7015 9011:70159006:7016 9007:7016 9008:7016 9009:7016 9010:7016 9011:7016 9006:70179007:7017 9008:7017 9009:7017 9010:7017 9011:7017 9006:7018 9007:70189008:7018 9009:7018 9010:7018 9011:7018 9006:7019 9007:7019 9008:70199009:7019 9010:7019 9011:7019 9006:7020 9007:7020 9008:7020 9009:70209010:7020 9011:7020 9006:7021 9007:7021 9008:7021 9009:7021 9010:70219011:7021 9006:7022 9007:7022 9008:7022 9009:7022 9010:7022 9011:70229006:7023 9007:7023 9008:7023 9009:7023 9010:7023 9011:7023 9006:70249007:7024 9008:7024 9009:7024 9010:7024 9011:7024 9006:7025 9007:70259008:7025 9009:7025 9010:7025 9011:7025 9006:7026 9007:7026 9008:70269009:7026 9010:7026 9011:7026 9006:7027 9007:7027 9008:7027 9009:70279010:7027 9011:7027 9012:7000 9013:7000 9014:7000 9015:7000 9016:70009017:7000 9012:7001 9013:7001 9014:7001 9015:7001 9016:7001 9017:70019012:7002 9013:7002 9014:7002 9015:7002 9016:7002 9017:7002 9012:70039013:7003 9014:7003 9015:7003 9016:7003 9017:7003 9012:7004 9013:70049014:7004 9015:7004 9016:7004 9017:7004 9012:7005 9013:7005 9014:70059015:7005 9016:7005 9017:7005 9012:7006 9013:7006 9014:7006 9015:70069016:7006 9017:7006 9012:7007 9013:7007 9014:7007 9015:7007 9016:70079017:7007 9012:7008 9013:7008 9014:7008 9015:7008 9016:7008 9017:70089012:7009 9013:7009 9014:7009 9015:7009 9016:7009 9017:7009 9012:70109013:7010 9014:7010 9015:7010 9016:7010 9017:7010 9012:7011 9013:70119014:7011 9015:7011 9016:7011 9017:7011 9012:7012 9013:7012 9014:70129015:7012 9016:7012 9017:7012 9012:7013 9013:7013 9014:7013 9015:70139016:7013 9017:7013 9012:7014 9013:7014 9014:7014 9015:7014 9016:70149017:7014 9012:7015 9013:7015 9014:7015 9015:7015 9016:7015 9017:70159012:7016 9013:7016 9014:7016 9015:7016 9016:7016 9017:7016 9012:70179013:7017 9014:7017 9015:7017 9016:7017 9017:7017 9012:7018 9013:70189014:7018 9015:7018 9016:7018 9017:7018 9012:7019 9013:7019 9014:70199015:7019 9016:7019 9017:7019 9012:7020 9013:7020 9014:7020 9015:70209016:7020 9017:7020 9012:7021 9013:7021 9014:7021 9015:7021 9016:70219017:7021 9012:7022 9013:7022 9014:7022 9015:7022 9016:7022 9017:70229012:7023 9013:7023 9014:7023 9015:7023 9016:7023 9017:7023 9012:70249013:7024 9014:7024 9015:7024 9016:7024 9017:7024 9012:7025 9013:70259014:7025 9015:7025 9016:7025 9017:7025 9012:7026 9013:7026 9014:70269015:7026 9016:7026 9017:7026 9012:7027 9013:7027 9014:7027 9015:70279016:7027 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9076:7016 9077:7016 9072:70179073:7017 9074:7017 9075:7017 9076:7017 9077:7017 9072:7018 9073:70189074:7018 9075:7018 9076:7018 9077:7018 9072:7019 9073:7019 9074:70199075:7019 9076:7019 9077:7019 9072:7020 9073:7020 9074:7020 9075:70209076:7020 9077:7020 9072:7021 9073:7021 9074:7021 9075:7021 9076:70219077:7021 9072:7022 9073:7022 9074:7022 9075:7022 9076:7022 9077:70229072:7023 9073:7023 9074:7023 9075:7023 9076:7023 9077:7023 9072:70249073:7024 9074:7024 9075:7024 9076:7024 9077:7024 9072:7025 9073:70259074:7025 9075:7025 9076:7025 9077:7025 9072:7026 9073:7026 9074:70269075:7026 9076:7026 9077:7026 9072:7027 9073:7027 9074:7027 9075:70279076:7027 9077:7027 9078:7000 9079:7000 9080:7000 9081:7000 9082:70009083:7000 9078:7001 9079:7001 9080:7001 9081:7001 9082:7001 9083:70019078:7002 9079:7002 9080:7002 9081:7002 9082:7002 9083:7002 9078:70039079:7003 9080:7003 9081:7003 9082:7003 9083:7003 9078:7004 9079:70049080:7004 9081:7004 9082:7004 9083:7004 9078:7005 9079:7005 9080:70059081:7005 9082:7005 9083:7005 9078:7006 9079:7006 9080:7006 9081:70069082:7006 9083:7006 9078:7007 9079:7007 9080:7007 9081:7007 9082:70079083:7007 9078:7008 9079:7008 9080:7008 9081:7008 9082:7008 9083:70089078:7009 9079:7009 9080:7009 9081:7009 9082:7009 9083:7009 9078:70109079:7010 9080:7010 9081:7010 9082:7010 9083:7010 9078:7011 9079:70119080:7011 9081:7011 9082:7011 9083:7011 9078:7012 9079:7012 9080:70129081:7012 9082:7012 9083:7012 9078:7013 9079:7013 9080:7013 9081:70139082:7013 9083:7013 9078:7014 9079:7014 9080:7014 9081:7014 9082:70149083:7014 9078:7015 9079:7015 9080:7015 9081:7015 9082:7015 9083:70159078:7016 9079:7016 9080:7016 9081:7016 9082:7016 9083:7016 9078:70179079:7017 9080:7017 9081:7017 9082:7017 9083:7017 9078:7018 9079:70189080:7018 9081:7018 9082:7018 9083:7018 9078:7019 9079:7019 9080:70199081:7019 9082:7019 9083:7019 9078:7020 9079:7020 9080:7020 9081:70209082:7020 9083:7020 9078:7021 9079:7021 9080:7021 9081:7021 9082:70219083:7021 9078:7022 9079:7022 9080:7022 9081:7022 9082:7022 9083:70229078:7023 9079:7023 9080:7023 9081:7023 9082:7023 9083:7023 9078:70249079:7024 9080:7024 9081:7024 9082:7024 9083:7024 9078:7025 9079:70259080:7025 9081:7025 9082:7025 9083:7025 9078:7026 9079:7026 9080:70269081:7026 9082:7026 9083:7026 9078:7027 9079:7027 9080:7027 9081:70279082:7027 9083:7027 9084:7000 9085:7000 9086:7000 9087:7000 9088:70009089:7000 9084:7001 9085:7001 9086:7001 9087:7001 9088:7001 9089:70019084:7002 9085:7002 9086:7002 9087:7002 9088:7002 9089:7002 9084:70039085:7003 9086:7003 9087:7003 9088:7003 9089:7003 9084:7004 9085:70049086:7004 9087:7004 9088:7004 9089:7004 9084:7005 9085:7005 9086:70059087:7005 9088:7005 9089:7005 9084:7006 9085:7006 9086:7006 9087:70069088:7006 9089:7006 9084:7007 9085:7007 9086:7007 9087:7007 9088:70079089:7007 9084:7008 9085:7008 9086:7008 9087:7008 9088:7008 9089:70089084:7009 9085:7009 9086:7009 9087:7009 9088:7009 9089:7009 9084:70109085:7010 9086:7010 9087:7010 9088:7010 9089:7010 9084:7011 9085:70119086:7011 9087:7011 9088:7011 9089:7011 9084:7012 9085:7012 9086:70129087:7012 9088:7012 9089:7012 9084:7013 9085:7013 9086:7013 9087:70139088:7013 9089:7013 9084:7014 9085:7014 9086:7014 9087:7014 9088:70149089:7014 9084:7015 9085:7015 9086:7015 9087:7015 9088:7015 9089:70159084:7016 9085:7016 9086:7016 9087:7016 9088:7016 9089:7016 9084:70179085:7017 9086:7017 9087:7017 9088:7017 9089:7017 9084:7018 9085:70189086:7018 9087:7018 9088:7018 9089:7018 9084:7019 9085:7019 9086:70199087:7019 9088:7019 9089:7019 9084:7020 9085:7020 9086:7020 9087:70209088:7020 9089:7020 9084:7021 9085:7021 9086:7021 9087:7021 9088:70219089:7021 9084:7022 9085:7022 9086:7022 9087:7022 9088:7022 9089:70229084:7023 9085:7023 9086:7023 9087:7023 9088:7023 9089:7023 9084:70249085:7024 9086:7024 9087:7024 9088:7024 9089:7024 9084:7025 9085:70259086:7025 9087:7025 9088:7025 9089:7025 9084:7026 9085:7026 9086:70269087:7026 9088:7026 9089:7026 9084:7027 9085:7027 9086:7027 9087:70279088:7027 9089:7027 9090:7000 9091:7000 9092:7000 9093:7000 9094:70009095:7000 9090:7001 9091:7001 9092:7001 9093:7001 9094:7001 9095:70019090:7002 9091:7002 9092:7002 9093:7002 9094:7002 9095:7002 9090:70039091:7003 9092:7003 9093:7003 9094:7003 9095:7003 9090:7004 9091:70049092:7004 9093:7004 9094:7004 9095:7004 9090:7005 9091:7005 9092:70059093:7005 9094:7005 9095:7005 9090:7006 9091:7006 9092:7006 9093:70069094:7006 9095:7006 9090:7007 9091:7007 9092:7007 9093:7007 9094:70079095:7007 9090:7008 9091:7008 9092:7008 9093:7008 9094:7008 9095:70089090:7009 9091:7009 9092:7009 9093:7009 9094:7009 9095:7009 9090:70109091:7010 9092:7010 9093:7010 9094:7010 9095:7010 9090:7011 9091:70119092:7011 9093:7011 9094:7011 9095:7011 9090:7012 9091:7012 9092:70129093:7012 9094:7012 9095:7012 9090:7013 9091:7013 9092:7013 9093:70139094:7013 9095:7013 9090:7014 9091:7014 9092:7014 9093:7014 9094:70149095:7014 9090:7015 9091:7015 9092:7015 9093:7015 9094:7015 9095:70159090:7016 9091:7016 9092:7016 9093:7016 9094:7016 9095:7016 9090:70179091:7017 9092:7017 9093:7017 9094:7017 9095:7017 9090:7018 9091:70189092:7018 9093:7018 9094:7018 9095:7018 9090:7019 9091:7019 9092:70199093:7019 9094:7019 9095:7019 9090:7020 9091:7020 9092:7020 9093:70209094:7020 9095:7020 9090:7021 9091:7021 9092:7021 9093:7021 9094:70219095:7021 9090:7022 9091:7022 9092:7022 9093:7022 9094:7022 9095:70229090:7023 9091:7023 9092:7023 9093:7023 9094:7023 9095:7023 9090:70249091:7024 9092:7024 9093:7024 9094:7024 9095:7024 9090:7025 9091:70259092:7025 9093:7025 9094:7025 9095:7025 9090:7026 9091:7026 9092:70269093:7026 9094:7026 9095:7026 9090:7027 9091:7027 9092:7027 9093:70279094:7027 9095:7027 9096:7000 9097:7000 9098:7000 9099:7000 9100:70009101:7000 9096:7001 9097:7001 9098:7001 9099:7001 9100:7001 9101:70019096:7002 9097:7002 9098:7002 9099:7002 9100:7002 9101:7002 9096:70039097:7003 9098:7003 9099:7003 9100:7003 9101:7003 9096:7004 9097:70049098:7004 9099:7004 9100:7004 9101:7004 9096:7005 9097:7005 9098:70059099:7005 9100:7005 9101:7005 9096:7006 9097:7006 9098:7006 9099:70069100:7006 9101:7006 9096:7007 9097:7007 9098:7007 9099:7007 9100:70079101:7007 9096:7008 9097:7008 9098:7008 9099:7008 9100:7008 9101:70089096:7009 9097:7009 9098:7009 9099:7009 9100:7009 9101:7009 9096:70109097:7010 9098:7010 9099:7010 9100:7010 9101:7010 9096:7011 9097:70119098:7011 9099:7011 9100:7011 9101:7011 9096:7012 9097:7012 9098:70129099:7012 9100:7012 9101:7012 9096:7013 9097:7013 9098:7013 9099:70139100:7013 9101:7013 9096:7014 9097:7014 9098:7014 9099:7014 9100:70149101:7014 9096:7015 9097:7015 9098:7015 9099:7015 9100:7015 9101:70159096:7016 9097:7016 9098:7016 9099:7016 9100:7016 9101:7016 9096:70179097:7017 9098:7017 9099:7017 9100:7017 9101:7017 9096:7018 9097:70189098:7018 9099:7018 9100:7018 9101:7018 9096:7019 9097:7019 9098:70199099:7019 9100:7019 9101:7019 9096:7020 9097:7020 9098:7020 9099:70209100:7020 9101:7020 9096:7021 9097:7021 9098:7021 9099:7021 9100:70219101:7021 9096:7022 9097:7022 9098:7022 9099:7022 9100:7022 9101:70229096:7023 9097:7023 9098:7023 9099:7023 9100:7023 9101:7023 9096:70249097:7024 9098:7024 9099:7024 9100:7024 9101:7024 9096:7025 9097:70259098:7025 9099:7025 9100:7025 9101:7025 9096:7026 9097:7026 9098:70269099:7026 9100:7026 9101:7026 9096:7027 9097:7027 9098:7027 9099:70279100:7027 9101:7027 9102:7000 9103:7000 9104:7000 9105:7000 — —9102:7001 9103:7001 9104:7001 9105:7001 9102:7002 9103:7002 9104:70029105:7002 9102:7003 9103:7003 9104:7003 9105:7003 9102:7004 9103:70049104:7004 9105:7004 9102:7005 9103:7005 9104:7005 9105:7005 9102:70069103:7006 9104:7006 9105:7006 9102:7007 9103:7007 9104:7007 9105:70079102:7008 9103:7008 9104:7008 9105:7008 9102:7009 9103:7009 9104:70099105:7009 9102:7010 9103:7010 9104:7010 9105:7010 9102:7011 9103:70119104:7011 9105:7011 9102:7012 9103:7012 9104:7012 9105:7012 9102:70139103:7013 9104:7013 9105:7013 9102:7014 9103:7014 9104:7014 9105:70149102:7015 9103:7015 9104:7015 9105:7015 9102:7016 9103:7016 9104:70169105:7016 9102:7017 9103:7017 9104:7017 9105:7017 9102:7018 9103:70189104:7018 9105:7018 9102:7019 9103:7019 9104:7019 9105:7019 9102:70209103:7020 9104:7020 9105:7020 9102:7021 9103:7021 9104:7021 9105:70219102:7022 9103:7022 9104:7022 9105:7022 9102:7023 9103:7023 9104:70239105:7023 9102:7024 9103:7024 9104:7024 9105:7024 9102:7025 9103:70259104:7025 9105:7025 9102:7026 9103:7026 9104:7026 9105:7026 9102:70279103:7027 9104:7027 9105:7027

TABLE D Example combinations of a compound X with a compound Y. X:Y X:YX:Y X:Y X:Y X:Y 6000:9000 6040:9000 6000:9001 6040:9001 6000:90026040:9002 6001:9000 6041:9000 6001:9001 6041:9001 6001:9002 6041:90026002:9000 6042:9000 6002:9001 6042:9001 6002:9002 6042:9002 6003:90006043:9000 6003:9001 6043:9001 6003:9002 6043:9002 6004:9000 6044:90006004:9001 6044:9001 6004:9002 6044:9002 6005:9000 6045:9000 6005:90016045:9001 6005:9002 6045:9002 6006:9000 6046:9000 6006:9001 6046:90016006:9002 6046:9002 6007:9000 6047:9000 6007:9001 6047:9001 6007:90026047:9002 6008:9000 6048:9000 6008:9001 6048:9001 6008:9002 6048:90026009:9000 6049:9000 6009:9001 6049:9001 6009:9002 6049:9002 6010:90006050:9000 6010:9001 6050:9001 6010:9002 6050:9002 6011:9000 6051:90006011:9001 6051:9001 6011:9002 6051:9002 6012:9000 6052:9000 6012:90016052:9001 6012:9002 6052:9002 6013:9000 6053:9000 6013:9001 6053:90016013:9002 6053:9002 6014:9000 6054:9000 6014:9001 6054:9001 6014:90026054:9002 6015:9000 6055:9000 6015:9001 6055:9001 6015:9002 6055:90026016:9000 6056:9000 6016:9001 6056:9001 6016:9002 6056:9002 6017:90006057:9000 6017:9001 6057:9001 6017:9002 6057:9002 6018:9000 6058:90006018:9001 6058:9001 6018:9002 6058:9002 6019:9000 6059:9000 6019:90016059:9001 6019:9002 6059:9002 6020:9000 6060:9000 6020:9001 6060:90016020:9002 6060:9002 6021:9000 6061:9000 6021:9001 6061:9001 6021:90026061:9002 6022:9000 6062:9000 6022:9001 6062:9001 6022:9002 6062:90026023:9000 6063:9000 6023:9001 6063:9001 6023:9002 6063:9002 6024:90006064:9000 6024:9001 6064:9001 6024:9002 6064:9002 6025:9000 6065:90006025:9001 6065:9001 6025:9002 6065:9002 6026:9000 6066:9000 6026:90016066:9001 6026:9002 6066:9002 6027:9000 6067:9000 6027:9001 6067:90016027:9002 6067:9002 6028:9000 6068:9000 6028:9001 6068:9001 6028:90026068:9002 6029:9000 6069:9000 6029:9001 6069:9001 6029:9002 6069:90026030:9000 6070:9000 6030:9001 6070:9001 6030:9002 6070:9002 6031:90006071:9000 6031:9001 6071:9001 6031:9002 6071:9002 6032:9000 6072:90006032:9001 6072:9001 6032:9002 6072:9002 6033:9000 6073:9000 6033:90016073:9001 6033:9002 6073:9002 6034:9000 6074:9000 6034:9001 6074:90016034:9002 6074:9002 6035:9000 6075:9000 6035:9001 6075:9001 6035:90026075:9002 6036:9000 6076:9000 6036:9001 6076:9001 6036:9002 6076:90026037:9000 6077:9000 6037:9001 6077:9001 6037:9002 6077:9002 6038:90006078:9000 6038:9001 6078:9001 6038:9002 6078:9002 6039:9000 6039:90016039:9002 6000:9003 6040:9003 6000:9004 6040:9004 6000:9005 6040:90056001:9003 6041:9003 6001:9004 6041:9004 6001:9005 6041:9005 6002:90036042:9003 6002:9004 6042:9004 6002:9005 6042:9005 6003:9003 6043:90036003:9004 6043:9004 6003:9005 6043:9005 6004:9003 6044:9003 6004:90046044:9004 6004:9005 6044:9005 6005:9003 6045:9003 6005:9004 6045:90046005:9005 6045:9005 6006:9003 6046:9003 6006:9004 6046:9004 6006:90056046:9005 6007:9003 6047:9003 6007:9004 6047:9004 6007:9005 6047:90056008:9003 6048:9003 6008:9004 6048:9004 6008:9005 6048:9005 6009:90036049:9003 6009:9004 6049:9004 6009:9005 6049:9005 6010:9003 6050:90036010:9004 6050:9004 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6035:9094 6075:9094 6035:9095 6075:9095 6036:9093 6076:90936036:9094 6076:9094 6036:9095 6076:9095 6037:9093 6077:9093 6037:90946077:9094 6037:9095 6077:9095 6038:9093 6078:9093 6038:9094 6078:90946038:9095 6078:9095 6039:9093 6039:9094 6039:9095 6000:9096 6040:90966000:9097 6040:9097 6000:9098 6040:9098 6001:9096 6041:9096 6001:90976041:9097 6001:9098 6041:9098 6002:9096 6042:9096 6002:9097 6042:90976002:9098 6042:9098 6003:9096 6043:9096 6003:9097 6043:9097 6003:90986043:9098 6004:9096 6044:9096 6004:9097 6044:9097 6004:9098 6044:90986005:9096 6045:9096 6005:9097 6045:9097 6005:9098 6045:9098 6006:90966046:9096 6006:9097 6046:9097 6006:9098 6046:9098 6007:9096 6047:90966007:9097 6047:9097 6007:9098 6047:9098 6008:9096 6048:9096 6008:90976048:9097 6008:9098 6048:9098 6009:9096 6049:9096 6009:9097 6049:90976009:9098 6049:9098 6010:9096 6050:9096 6010:9097 6050:9097 6010:90986050:9098 6011:9096 6051:9096 6011:9097 6051:9097 6011:9098 6051:90986012:9096 6052:9096 6012:9097 6052:9097 6012:9098 6052:9098 6013:90966053:9096 6013:9097 6053:9097 6013:9098 6053:9098 6014:9096 6054:90966014:9097 6054:9097 6014:9098 6054:9098 6015:9096 6055:9096 6015:90976055:9097 6015:9098 6055:9098 6016:9096 6056:9096 6016:9097 6056:90976016:9098 6056:9098 6017:9096 6057:9096 6017:9097 6057:9097 6017:90986057:9098 6018:9096 6058:9096 6018:9097 6058:9097 6018:9098 6058:90986019:9096 6059:9096 6019:9097 6059:9097 6019:9098 6059:9098 6020:90966060:9096 6020:9097 6060:9097 6020:9098 6060:9098 6021:9096 6061:90966021:9097 6061:9097 6021:9098 6061:9098 6022:9096 6062:9096 6022:90976062:9097 6022:9098 6062:9098 6023:9096 6063:9096 6023:9097 6063:90976023:9098 6063:9098 6024:9096 6064:9096 6024:9097 6064:9097 6024:90986064:9098 6025:9096 6065:9096 6025:9097 6065:9097 6025:9098 6065:90986026:9096 6066:9096 6026:9097 6066:9097 6026:9098 6066:9098 6027:90966067:9096 6027:9097 6067:9097 6027:9098 6067:9098 6028:9096 6068:90966028:9097 6068:9097 6028:9098 6068:9098 6029:9096 6069:9096 6029:90976069:9097 6029:9098 6069:9098 6030:9096 6070:9096 6030:9097 6070:90976030:9098 6070:9098 6031:9096 6071:9096 6031:9097 6071:9097 6031:90986071:9098 6032:9096 6072:9096 6032:9097 6072:9097 6032:9098 6072:90986033:9096 6073:9096 6033:9097 6073:9097 6033:9098 6073:9098 6034:90966074:9096 6034:9097 6074:9097 6034:9098 6074:9098 6035:9096 6075:90966035:9097 6075:9097 6035:9098 6075:9098 6036:9096 6076:9096 6036:90976076:9097 6036:9098 6076:9098 6037:9096 6077:9096 6037:9097 6077:90976037:9098 6077:9098 6038:9096 6078:9096 6038:9097 6078:9097 6038:90986078:9098 6039:9096 6039:9097 6039:9098 6000:9099 6040:9099 6000:91006040:9100 6000:9101 6040:9101 6001:9099 6041:9099 6001:9100 6041:91006001:9101 6041:9101 6002:9099 6042:9099 6002:9100 6042:9100 6002:91016042:9101 6003:9099 6043:9099 6003:9100 6043:9100 6003:9101 6043:91016004:9099 6044:9099 6004:9100 6044:9100 6004:9101 6044:9101 6005:90996045:9099 6005:9100 6045:9100 6005:9101 6045:9101 6006:9099 6046:90996006:9100 6046:9100 6006:9101 6046:9101 6007:9099 6047:9099 6007:91006047:9100 6007:9101 6047:9101 6008:9099 6048:9099 6008:9100 6048:91006008:9101 6048:9101 6009:9099 6049:9099 6009:9100 6049:9100 6009:91016049:9101 6010:9099 6050:9099 6010:9100 6050:9100 6010:9101 6050:91016011:9099 6051:9099 6011:9100 6051:9100 6011:9101 6051:9101 6012:90996052:9099 6012:9100 6052:9100 6012:9101 6052:9101 6013:9099 6053:90996013:9100 6053:9100 6013:9101 6053:9101 6014:9099 6054:9099 6014:91006054:9100 6014:9101 6054:9101 6015:9099 6055:9099 6015:9100 6055:91006015:9101 6055:9101 6016:9099 6056:9099 6016:9100 6056:9100 6016:91016056:9101 6017:9099 6057:9099 6017:9100 6057:9100 6017:9101 6057:91016018:9099 6058:9099 6018:9100 6058:9100 6018:9101 6058:9101 6019:90996059:9099 6019:9100 6059:9100 6019:9101 6059:9101 6020:9099 6060:90996020:9100 6060:9100 6020:9101 6060:9101 6021:9099 6061:9099 6021:91006061:9100 6021:9101 6061:9101 6022:9099 6062:9099 6022:9100 6062:91006022:9101 6062:9101 6023:9099 6063:9099 6023:9100 6063:9100 6023:91016063:9101 6024:9099 6064:9099 6024:9100 6064:9100 6024:9101 6064:91016025:9099 6065:9099 6025:9100 6065:9100 6025:9101 6065:9101 6026:90996066:9099 6026:9100 6066:9100 6026:9101 6066:9101 6027:9099 6067:90996027:9100 6067:9100 6027:9101 6067:9101 6028:9099 6068:9099 6028:91006068:9100 6028:9101 6068:9101 6029:9099 6069:9099 6029:9100 6069:91006029:9101 6069:9101 6030:9099 6070:9099 6030:9100 6070:9100 6030:91016070:9101 6031:9099 6071:9099 6031:9100 6071:9100 6031:9101 6071:91016032:9099 6072:9099 6032:9100 6072:9100 6032:9101 6072:9101 6033:90996073:9099 6033:9100 6073:9100 6033:9101 6073:9101 6034:9099 6074:90996034:9100 6074:9100 6034:9101 6074:9101 6035:9099 6075:9099 6035:91006075:9100 6035:9101 6075:9101 6036:9099 6076:9099 6036:9100 6076:91006036:9101 6076:9101 6037:9099 6077:9099 6037:9100 6077:9100 6037:91016077:9101 6038:9099 6078:9099 6038:9100 6078:9100 6038:9101 6078:91016039:9099 6039:9100 6039:9101 6000:9102 6040:9102 6000:9103 6040:91036000:9104 6040:9104 6001:9102 6041:9102 6001:9103 6041:9103 6001:91046041:9104 6002:9102 6042:9102 6002:9103 6042:9103 6002:9104 6042:91046003:9102 6043:9102 6003:9103 6043:9103 6003:9104 6043:9104 6004:91026044:9102 6004:9103 6044:9103 6004:9104 6044:9104 6005:9102 6045:91026005:9103 6045:9103 6005:9104 6045:9104 6006:9102 6046:9102 6006:91036046:9103 6006:9104 6046:9104 6007:9102 6047:9102 6007:9103 6047:91036007:9104 6047:9104 6008:9102 6048:9102 6008:9103 6048:9103 6008:91046048:9104 6009:9102 6049:9102 6009:9103 6049:9103 6009:9104 6049:91046010:9102 6050:9102 6010:9103 6050:9103 6010:9104 6050:9104 6011:91026051:9102 6011:9103 6051:9103 6011:9104 6051:9104 6012:9102 6052:91026012:9103 6052:9103 6012:9104 6052:9104 6013:9102 6053:9102 6013:91036053:9103 6013:9104 6053:9104 6014:9102 6054:9102 6014:9103 6054:91036014:9104 6054:9104 6015:9102 6055:9102 6015:9103 6055:9103 6015:91046055:9104 6016:9102 6056:9102 6016:9103 6056:9103 6016:9104 6056:91046017:9102 6057:9102 6017:9103 6057:9103 6017:9104 6057:9104 6018:91026058:9102 6018:9103 6058:9103 6018:9104 6058:9104 6019:9102 6059:91026019:9103 6059:9103 6019:9104 6059:9104 6020:9102 6060:9102 6020:91036060:9103 6020:9104 6060:9104 6021:9102 6061:9102 6021:9103 6061:91036021:9104 6061:9104 6022:9102 6062:9102 6022:9103 6062:9103 6022:91046062:9104 6023:9102 6063:9102 6023:9103 6063:9103 6023:9104 6063:91046024:9102 6064:9102 6024:9103 6064:9103 6024:9104 6064:9104 6025:91026065:9102 6025:9103 6065:9103 6025:9104 6065:9104 6026:9102 6066:91026026:9103 6066:9103 6026:9104 6066:9104 6027:9102 6067:9102 6027:91036067:9103 6027:9104 6067:9104 6028:9102 6068:9102 6028:9103 6068:91036028:9104 6068:9104 6029:9102 6069:9102 6029:9103 6069:9103 6029:91046069:9104 6030:9102 6070:9102 6030:9103 6070:9103 6030:9104 6070:91046031:9102 6071:9102 6031:9103 6071:9103 6031:9104 6071:9104 6032:91026072:9102 6032:9103 6072:9103 6032:9104 6072:9104 6033:9102 6073:91026033:9103 6073:9103 6033:9104 6073:9104 6034:9102 6074:9102 6034:91036074:9103 6034:9104 6074:9104 6035:9102 6075:9102 6035:9103 6075:91036035:9104 6075:9104 6036:9102 6076:9102 6036:9103 6076:9103 6036:91046076:9104 6037:9102 6077:9102 6037:9103 6077:9103 6037:9104 6077:91046038:9102 6078:9102 6038:9103 6078:9103 6038:9104 6078:9104 6039:91026039:9103 6039:9104 6000:9105 6040:9105 — — — — 6001:9105 6041:91056002:9105 6042:9105 6003:9105 6043:9105 6004:9105 6044:9105 6005:91056045:9105 6006:9105 6046:9105 6007:9105 6047:9105 6008:9105 6048:91056009:9105 6049:9105 6010:9105 6050:9105 6011:9105 6051:9105 6012:91056052:9105 6013:9105 6053:9105 6014:9105 6054:9105 6015:9105 6055:91056016:9105 6056:9105 6017:9105 6057:9105 6018:9105 6058:9105 6019:91056059:9105 6020:9105 6060:9105 6021:9105 6061:9105 6022:9105 6062:91056023:9105 6063:9105 6024:9105 6064:9105 6025:9105 6065:9105 6026:91056066:9105 6027:9105 6067:9105 6028:9105 6068:9105 6029:9105 6069:91056030:9105 6070:9105 6031:9105 6071:9105 6032:9105 6072:9105 6033:91056073:9105 6034:9105 6074:9105 6035:9105 6075:9105 6036:9105 6076:91056037:9105 6077:9105 6038:9105 6078:9105 6039:9105

TABLE E Example combinations of a compound X with a compound Y. X:Y X:YX:Y X:Y X:Y X:Y 8000:9000 8000:9001 8000:9002 8000:9003 8000:90048000:9005 8001:9000 8001:9001 8001:9002 8001:9003 8001:9004 8001:90058002:9000 8002:9001 8002:9002 8002:9003 8002:9004 8002:9005 8003:90008003:9001 8003:9002 8003:9003 8003:9004 8003:9005 8004:9000 8004:90018004:9002 8004:9003 8004:9004 8004:9005 8005:9000 8005:9001 8005:90028005:9003 8005:9004 8005:9005 8006:9000 8006:9001 8006:9002 8006:90038006:9004 8006:9005 8007:9000 8007:9001 8007:9002 8007:9003 8007:90048007:9005 8008:9000 8008:9001 8008:9002 8008:9003 8008:9004 8008:90058009:9000 8009:9001 8009:9002 8009:9003 8009:9004 8009:9005 8010:90008010:9001 8010:9002 8010:9003 8010:9004 8010:9005 8011:9000 8011:90018011:9002 8011:9003 8011:9004 8011:9005 8012:9000 8012:9001 8012:90028012:9003 8012:9004 8012:9005 8013:9000 8013:9001 8013:9002 8013:90038013:9004 8013:9005 8014:9000 8014:9001 8014:9002 8014:9003 8014:90048014:9005 8015:9000 8015:9001 8015:9002 8015:9003 8015:9004 8015:90058016:9000 8016:9001 8016:9002 8016:9003 8016:9004 8016:9005 8000:90068000:9007 8000:9008 8000:9009 8000:9010 8000:9011 8001:9006 8001:90078001:9008 8001:9009 8001:9010 8001:9011 8002:9006 8002:9007 8002:90088002:9009 8002:9010 8002:9011 8003:9006 8003:9007 8003:9008 8003:90098003:9010 8003:9011 8004:9006 8004:9007 8004:9008 8004:9009 8004:90108004:9011 8005:9006 8005:9007 8005:9008 8005:9009 8005:9010 8005:90118006:9006 8006:9007 8006:9008 8006:9009 8006:9010 8006:9011 8007:90068007:9007 8007:9008 8007:9009 8007:9010 8007:9011 8008:9006 8008:90078008:9008 8008:9009 8008:9010 8008:9011 8009:9006 8009:9007 8009:90088009:9009 8009:9010 8009:9011 8010:9006 8010:9007 8010:9008 8010:90098010:9010 8010:9011 8011:9006 8011:9007 8011:9008 8011:9009 8011:90108011:9011 8012:9006 8012:9007 8012:9008 8012:9009 8012:9010 8012:90118013:9006 8013:9007 8013:9008 8013:9009 8013:9010 8013:9011 8014:90068014:9007 8014:9008 8014:9009 8014:9010 8014:9011 8015:9006 8015:90078015:9008 8015:9009 8015:9010 8015:9011 8016:9006 8016:9007 8016:90088016:9009 8016:9010 8016:9011 8000:9012 8000:9013 8000:9014 8000:90158000:9016 8000:9017 8001:9012 8001:9013 8001:9014 8001:9015 8001:90168001:9017 8002:9012 8002:9013 8002:9014 8002:9015 8002:9016 8002:90178003:9012 8003:9013 8003:9014 8003:9015 8003:9016 8003:9017 8004:90128004:9013 8004:9014 8004:9015 8004:9016 8004:9017 8005:9012 8005:90138005:9014 8005:9015 8005:9016 8005:9017 8006:9012 8006:9013 8006:90148006:9015 8006:9016 8006:9017 8007:9012 8007:9013 8007:9014 8007:90158007:9016 8007:9017 8008:9012 8008:9013 8008:9014 8008:9015 8008:90168008:9017 8009:9012 8009:9013 8009:9014 8009:9015 8009:9016 8009:90178010:9012 8010:9013 8010:9014 8010:9015 8010:9016 8010:9017 8011:90128011:9013 8011:9014 8011:9015 8011:9016 8011:9017 8012:9012 8012:90138012:9014 8012:9015 8012:9016 8012:9017 8013:9012 8013:9013 8013:90148013:9015 8013:9016 8013:9017 8014:9012 8014:9013 8014:9014 8014:90158014:9016 8014:9017 8015:9012 8015:9013 8015:9014 8015:9015 8015:90168015:9017 8016:9012 8016:9013 8016:9014 8016:9015 8016:9016 8016:90178000:9018 8000:9019 8000:9020 8000:9021 8000:9022 8000:9023 8001:90188001:9019 8001:9020 8001:9021 8001:9022 8001:9023 8002:9018 8002:90198002:9020 8002:9021 8002:9022 8002:9023 8003:9018 8003:9019 8003:90208003:9021 8003:9022 8003:9023 8004:9018 8004:9019 8004:9020 8004:90218004:9022 8004:9023 8005:9018 8005:9019 8005:9020 8005:9021 8005:90228005:9023 8006:9018 8006:9019 8006:9020 8006:9021 8006:9022 8006:90238007:9018 8007:9019 8007:9020 8007:9021 8007:9022 8007:9023 8008:90188008:9019 8008:9020 8008:9021 8008:9022 8008:9023 8009:9018 8009:90198009:9020 8009:9021 8009:9022 8009:9023 8010:9018 8010:9019 8010:90208010:9021 8010:9022 8010:9023 8011:9018 8011:9019 8011:9020 8011:90218011:9022 8011:9023 8012:9018 8012:9019 8012:9020 8012:9021 8012:90228012:9023 8013:9018 8013:9019 8013:9020 8013:9021 8013:9022 8013:90238014:9018 8014:9019 8014:9020 8014:9021 8014:9022 8014:9023 8015:90188015:9019 8015:9020 8015:9021 8015:9022 8015:9023 8016:9018 8016:90198016:9020 8016:9021 8016:9022 8016:9023 8000:9024 8000:9025 8000:90268000:9027 8000:9028 8000:9029 8001:9024 8001:9025 8001:9026 8001:90278001:9028 8001:9029 8002:9024 8002:9025 8002:9026 8002:9027 8002:90288002:9029 8003:9024 8003:9025 8003:9026 8003:9027 8003:9028 8003:90298004:9024 8004:9025 8004:9026 8004:9027 8004:9028 8004:9029 8005:90248005:9025 8005:9026 8005:9027 8005:9028 8005:9029 8006:9024 8006:90258006:9026 8006:9027 8006:9028 8006:9029 8007:9024 8007:9025 8007:90268007:9027 8007:9028 8007:9029 8008:9024 8008:9025 8008:9026 8008:90278008:9028 8008:9029 8009:9024 8009:9025 8009:9026 8009:9027 8009:90288009:9029 8010:9024 8010:9025 8010:9026 8010:9027 8010:9028 8010:90298011:9024 8011:9025 8011:9026 8011:9027 8011:9028 8011:9029 8012:90248012:9025 8012:9026 8012:9027 8012:9028 8012:9029 8013:9024 8013:90258013:9026 8013:9027 8013:9028 8013:9029 8014:9024 8014:9025 8014:90268014:9027 8014:9028 8014:9029 8015:9024 8015:9025 8015:9026 8015:90278015:9028 8015:9029 8016:9024 8016:9025 8016:9026 8016:9027 8016:90288016:9029 8000:9030 8000:9031 8000:9032 8000:9033 8000:9034 8000:90358001:9030 8001:9031 8001:9032 8001:9033 8001:9034 8001:9035 8002:90308002:9031 8002:9032 8002:9033 8002:9034 8002:9035 8003:9030 8003:90318003:9032 8003:9033 8003:9034 8003:9035 8004:9030 8004:9031 8004:90328004:9033 8004:9034 8004:9035 8005:9030 8005:9031 8005:9032 8005:90338005:9034 8005:9035 8006:9030 8006:9031 8006:9032 8006:9033 8006:90348006:9035 8007:9030 8007:9031 8007:9032 8007:9033 8007:9034 8007:90358008:9030 8008:9031 8008:9032 8008:9033 8008:9034 8008:9035 8009:90308009:9031 8009:9032 8009:9033 8009:9034 8009:9035 8010:9030 8010:90318010:9032 8010:9033 8010:9034 8010:9035 8011:9030 8011:9031 8011:90328011:9033 8011:9034 8011:9035 8012:9030 8012:9031 8012:9032 8012:90338012:9034 8012:9035 8013:9030 8013:9031 8013:9032 8013:9033 8013:90348013:9035 8014:9030 8014:9031 8014:9032 8014:9033 8014:9034 8014:90358015:9030 8015:9031 8015:9032 8015:9033 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8013:9094 8013:9095 8014:90908014:9091 8014:9092 8014:9093 8014:9094 8014:9095 8015:9090 8015:90918015:9092 8015:9093 8015:9094 8015:9095 8016:9090 8016:9091 8016:90928016:9093 8016:9094 8016:9095 8000:9096 8000:9097 8000:9098 8000:90998000:9100 8000:9101 8001:9096 8001:9097 8001:9098 8001:9099 8001:91008001:9101 8002:9096 8002:9097 8002:9098 8002:9099 8002:9100 8002:91018003:9096 8003:9097 8003:9098 8003:9099 8003:9100 8003:9101 8004:90968004:9097 8004:9098 8004:9099 8004:9100 8004:9101 8005:9096 8005:90978005:9098 8005:9099 8005:9100 8005:9101 8006:9096 8006:9097 8006:90988006:9099 8006:9100 8006:9101 8007:9096 8007:9097 8007:9098 8007:90998007:9100 8007:9101 8008:9096 8008:9097 8008:9098 8008:9099 8008:91008008:9101 8009:9096 8009:9097 8009:9098 8009:9099 8009:9100 8009:91018010:9096 8010:9097 8010:9098 8010:9099 8010:9100 8010:9101 8011:90968011:9097 8011:9098 8011:9099 8011:9100 8011:9101 8012:9096 8012:90978012:9098 8012:9099 8012:9100 8012:9101 8013:9096 8013:9097 8013:90988013:9099 8013:9100 8013:9101 8014:9096 8014:9097 8014:9098 8014:90998014:9100 8014:9101 8015:9096 8015:9097 8015:9098 8015:9099 8015:91008015:9101 8016:9096 8016:9097 8016:9098 8016:9099 8016:9100 8016:91018000:9102 8000:9103 8000:9104 8000:9105 — — 8001:9102 8001:91038001:9104 8001:9105 8002:9102 8002:9103 8002:9104 8002:9105 8003:91028003:9103 8003:9104 8003:9105 8004:9102 8004:9103 8004:9104 8004:91058005:9102 8005:9103 8005:9104 8005:9105 8006:9102 8006:9103 8006:91048006:9105 8007:9102 8007:9103 8007:9104 8007:9105 8008:9102 8008:91038008:9104 8008:9105 8009:9102 8009:9103 8009:9104 8009:9105 8010:91028010:9103 8010:9104 8010:9105 8011:9102 8011:9103 8011:9104 8011:91058012:9102 8012:9103 8012:9104 8012:9105 8013:9102 8013:9103 8013:91048013:9105 8014:9102 8014:9103 8014:9104 8014:9105 8015:9102 8015:91038015:9104 8015:9105 8016:9102 8016:9103 8016:9104 8016:9105

EXAMPLES

Additional embodiments are disclosed in further detail in the followingexamples, which are not in any way intended to limit the scope of theclaims.

Example 1 2′-C-Methyl-4′-Fluorouridine 1

To a stirred suspension of 1-1 (20 g, 77.5 mmol), PPh₃ (30 g, 114.5mmol), imidazole (10 g, 147 mmol) and pyridine (90 mL) in anhydrous THF(300 mL) was added a solution of I₂ (25 g, 98.4 mmol) in THF (100 mL)dropwise at 0° C. The mixture was warmed to room temperature (R.T.) andstirred at R.T. for 10 h. The reaction was quenched by MeOH (100 mL).The solvent was removed, and the residue was re-dissolved in a mixtureethyl acetate (EA) and THF (2 L, 10:1). The organic phase was washedwith saturated Na₂S₂O₃ aq., and the aqueous phase was extracted with amixture of EA and THF (2 L, 10:1). The organic layer was combined andconcentrated to give a residue, which was purified on a silica gelcolumn (0-10% MeOH in DCM) to give 1-2 (22.5 g, 78.9%) as a white solid.¹H NMR: (DMSO-d₆, 400 MHz) δ 11.42 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 5.82(s, 1H), 5.63 (d, J=8.0 Hz, 1H), 5.50 (s, 1H), 5.23 (s, 1H), 3.77-3.79(m, 1H), 3.40-3.62 (m, 3H), 0.97 (s, 3H).

To a stirred solution of 1-2 (24.3 g, 66.03 mmol) in anhydrous MeOH (240mL) was added NaOMe (10.69 g, 198.09 mmol) at R.T. under N₂. The mixturewas refluxed for 3 h. The solvent was removed, and the residue wasre-dissolved in anhydrous pyridine (200 mL). To the mixture was addedAc₂O (84.9 g, 833.3 mmol) at 0° C. The mixture was warmed to 60° C. andstirred for 10 h. The solvent was removed, and the residue was dilutedwith DCM, washed with saturated NaHCO₃ and brine. The organic layer wasconcentrated and purified on a silica gel column (10-50% EA in PE) togive 1-3 (15 g, 70.1%) as a white solid. ¹H NMR: (CDCl₃, 400 MHz) δ 8.82(s, 1H), 7.23 (d, J=2.0 Hz, 1H), 6.54 (s, 1H), 5.85 (s, 1H), 5.77 (dd,J=8.0, 2.0 Hz, 1H), 4.69 (d, J=2.4 Hz, 1H), 4.58 (d, J=2.8 Hz, 1H), 2.07(d, J=5.2 Hz, 6H), 1.45 (s, 3H).

To an ice-cooled solution of 1-3 (15 g, 46.29 mmol) in anhydrous DCM(300 mL) was added AgF (29.39 g, 231.4 mmol). I₂ (23.51 g, 92.58 mmol)in anhydrous DCM (1.0 L) was added dropwise to the solution. Thereaction mixture was stirred at R.T. for 5 h. The reaction was quenchedwith saturated Na₂S₂O₃ and NaHCO₃, and extracted with DCM. The organiclayer was separated, dried and evaporated to dryness. The residue waspurified on a silica gel column (10-30% EA in PE) to give 1-4 (9.5 g,43.6%) as a white solid. ¹H NMR: (Methanol-d₄, 400 MHz) δ 7.52 (d, J=8.0Hz, 1H), 6.21 (s, 1H), 5.80 (d, J=17.2 Hz, 1H), 5.73 (d, J=8.0 Hz, 1H),3.58 (s, 1H), 3.54 (d, J=6.8 Hz, 1H), 2.17 (s, 3H), 2.09 (s, 3H), 1.58(s, 3H).

To a solution of 1-4 (7.0 g, 14.89 mmol) in anhydrous DMF (400 mL) wereadded NaOBz (21.44 g, 148.9 mmol) and 15-crown-5 (32.75 g, 148.9 mmol).The reaction mixture was stirred at 130° C. for 6 h. The solvent wasremoved, diluted with EA and washed with water and brine. The organiclayer was evaporated and purified on a silica gel column (10-30% EA inPE) to give 1-5 (2.8 g, 40.5%). ¹H NMR: (CDCl₃, 400 MHz) δ 8.84 (s, 1H),8.04-8.06 (m, 2H), 7.59 (t, J=7.2 Hz, 1H), 7.44-7.47 (m, 2H), 7.21-7.26(m, 1H), 6.21 (s, 1H), 5.85 (d, J=18 Hz, 1H), 5.67 (d, J=8.0 Hz, 1H),4.59-4.72 (m, 2H), 2.14 (s, 6H), 1.64 (d, J=6.0 Hz, 3H). ESI-MS: m/z444.9 [M−F+H]⁺.

A mixture of 1-5 (4.0 g; 8.6 mmol) and liquid ammonia was kept overnightat R. T. in a high-pressure stainless-steel vessel. Ammonia was thenevaporated, and the residue purified on silica (50 g column) with aCH₂Cl₂/MeOH solvent mixture (4-12% gradient) to yield compound 1 as acolorless foam (2.0 g; 84% yield). ESI-MS: m/z 275.1 [M−H]⁻.

Example 2 Compound 2

To a solution of 1 (1.2 g; 4.3 mmol) in dioxane (30 mL) were addedp-toluenesulphonic acid monohydrate (820 mg; 1 eq.) and trimethylorthoformate (14 mL; 30 eq.). The mixture was stirred overnight at R.T.The mixture was then neutralized with methanolic ammonia and the solventevaporated. Purification on silica gel column with CH₂Cl₂-MeOH solventsystem (4-10% gradient) yielded 2-1 (1.18 g, 87%).

To an ice cold solution of 2-1 (0.91 g; 2.9 mmol) in anhydrous THF (20mL) was added iso-propylmagnesium chloride (2.1 mL; 2 M in THF). Themixture was stirred at 0° C. for 20 mins. A solution ofphosphorochloridate reagent (2.2 g; 2.5 eq.) in THF (2 mL) was addeddropwise. The mixture was stirred overnight at R.T. The reaction wasquenched with saturated aq. NH₄Cl solution and stirred at R.T. for 10mins. The mixture was then diluted with water and CH₂Cl₂, and the twolayers were separated. The organic layer was washed with water, halfsaturated aq. NaHCO₃ and brine, and dried with Na₂SO₄. The evaporatedresidue was purified on silica gel column with CH₂Cl₂-iPrOH solventsystem (4-10% gradient) to yield Rp/Sp-mixture of 2-2 (1.59 g; 93%).

A mixture of 2-2 (1.45 g; 2.45 mmol) and 80% aq. HCOOH (7 mL) wasstirred at R.T. for 1.5 h. The solvent was evaporated and coevaporatedwith toluene. The obtained residue was dissolved in MeOH, treated withEt₃N (3 drops) and the solvent was evaporated. Purification on silicagel column with CH₂Cl₂-MeOH solvent system (4-10% gradient) yieldedRp/Sp-mixture of compound 2 (950 mg; 70%). ³¹P-NMR (DMSO-d₆): δ 3.52,3.47. MS: m/z=544 [M−1]⁻.

Example 3 Compound 3

To an ice cold solution of 3-1 (80 mg; 015 mmol) in anhydrous THF (2 mL)was added isopropylmagnesium chloride (0.22 mL; 2 M in THF). The mixturewas stirred at 0° C. for 20 mins. A solution of the phosphorochloridatereagent (0.16 g; 0.45 mmol) in THF (0.5 mL) was added dropwise. Themixture was stirred overnight at R.T. The reaction was quenched withsaturated aq. NH₄Cl solution and stirred at R.T. for 10 mins. Themixture was diluted with water and CH₂Cl₂, and the two layers wereseparated. The organic layer was washed with water, half saturated aq.NaHCO₃ and brine, and dried with Na₂SO₄. The evaporated residue waspurified on silica gel column with CH₂Cl₂-MeOH solvent system (2-10%gradient) to yield Rp/Sp-mixture of 3-2 (102 mg; 80%).

A mixture of 3-2 (100 mg; 0.12 mmol) in EtOH (3 mL) and 10% Pd/C (10 mg)was stirred under the H₂ atmosphere for 1.5 h. The mixture was filteredthrough a Celite pad, evaporated and purified on silica gel column withCH₂Cl₂-MeOH solvent system (4-10% gradient) to yield Rp/Sp-mixture ofcompound 3 (52 mg, 74%). ³¹P-NMR (DMSO-d₆): δ 3.51, 3.48. MS: m/z=584[M−1]⁻.

Example 4 Compounds 4 and 6

Dry 1 (14 mg, 0.05 mmol) was dissolved in the mixture of PO(OMe)₃ (0.750mL) and pyridine (0.5 mL). The mixture was evaporated in vacuum for 15mins at bath temperature 42° C., and then cooled down to R.T.N-Methylimidazole (0.009 mL, 0.11 mmol) was added followed by POCl₃(0.009 mL, 0.1 mmol). The mixture was kept at R.T. for 45 mins.Tributylamine (0.065 mL, 0.3 mmol) and N-tetrabutyl ammonium salt ofpyrophosphate (100 mg) was added. About 1 mL of dry DMF was added to geta homogeneous solution. In 1 h, the reaction was quenched with 2Mammonium acetate buffer (1 mL, pH=7.5), diluted water (10 mL) and loadedon a column HiLoad 16/10 with Q Sepharose High Performance. Theseparation was done in linear gradient of NaCl from 0 to 1N in 50 mMTRIS-buffer (pH7.5). The fractions eluted at 60% buffer B containedCompound 4 and at 80% buffer B contained Compound 6. The correspondingfractions were concentrated, and the residue purified by RP HPLC onSynergy 4 micron Hydro-RP column (Phenominex). A linear gradient ofmethanol from 0 to 30% in 50 mM triethylammonium acetate buffer (pH 7.5)was used for elution. The corresponding fractions were combined,concentrated and lyophilized 3 times to remove excess of buffer.Compound 4: ³¹P-NMR (D₂O): −3.76 (s); MS: m/z 355.3 [M−H]⁻. Compound 6:³¹P-NMR (D₂O): −9.28 (d, 1H, Pα), −12.31 (d, 1H, Pγ), −22.95 (t, 1H,Pβ); MS: m/z 515.0 [M−1]⁻.

Example 5 Compound 5

Compound 5 was synthesized as described for 2 on 0.1 mmol scale and withneopentyl ester of phosphorochloridate reagent. Yield was 36 mg (63%).³¹P-NMR (CDCl₃): δ 2.57 (s), 2.43 (s). MS: 572.6 [M−1]⁻.

Example 6 Compound 7

Dry 1 (14 mg, 0.05 mmol) was dissolved in the mixture of PO(OMe)₃ (0.750mL) and pyridine (0.5 mL). The mixture was evaporated in vacuum for 15mins at bath temperature 42° C., and then cooled down to R.T.N-Methylimidazole (0.009 mL, 0.11 mmol) was added followed by PSCl₃(0.01 mL, 0.1 mmol). The mixture was kept at R.T. for 1 h. Tributylamine(0.065 mL, 0.3 mmol) and N-tetrabutyl ammonium salt of pyrophosphate(200 mg) was added. About 1 mL of dry DMF was added to get a homogeneoussolution. In 2 h, the reaction was quenched with 2M ammonium acetatebuffer (1 mL, pH=7.5), diluted with water (10 mL) and loaded on a columnHiLoad 16/10 with Q Sepharose High Performance. Separation was done inlinear gradient of NaCl from 0 to 1N in 50 mM TRIS-buffer (pH7.5). Thefractions eluted at 80% buffer B contained 7 (compounds 7a and 7b). Thecorresponding fractions were concentrated, and the residue purified byRP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A lineargradient of methanol from 0 to 20% in 50 mM triethylammonium acetatebuffer (pH 7.5) was used for elution. Two peaks were collected. Thecorresponding fractions were combined, concentrated and lyophilized 3times to remove excess of buffer. Peak 1 (more polar): ³¹P-NMR (D₂O):+42.68 (d, 1H, Pα), −9.05 (d, 1H, Pγ), −22.95 (t, 1H, Pβ); MS 530.90[M−1]⁻. Peak 2 (less polar): ³¹P-NMR (D₂O): +42.78 (d, 1H, Pα), −10.12(bs, 1H, Pγ), −23.94 (t, 1H, Pβ); and MS 530.90 [M−1]⁻.

Example 7 Compound 23

To a stirred suspension of 23-1 (20.0 g, 81.3 mmol), imidazole (15.9 g,234.0 mmol), PPh₃ (53.5 g, 203.3 mmol) and pyridine (90 mL) in anhydrousTHF (100 mL) was added a solution of I₂ (41.3 g, 162.6 mmol) in THF (150mL) dropwise at 0° C. The mixture was slowly warmed to R.T. and stirredfor 14 h. The reaction was quenched with sat. aq. Na₂S₂O₃ (150 mL) andextracted with THF/EA (1/1) (100 mL×3). The organic layer was dried overNa₂SO₄, and concentrated at a low pressure. The residue wasrecrystallized from EtOH to afford pure 23-2 (23 g, 79%) as a whitesolid.

To a stirred solution of 23-2 (23 g, 65 mmol) in anhydrous MeOH (200 mL)was added NaOCH₃ (10.5 g, 195 mmol) in MeOH (50 mL) at R.T. The mixturewas stirred at 60° C. for 3 h, and quenched with dry ice. A solidprecipitated and removed by filtration. The filtrate was concentrated ata low pressure. The residue was purified on column silica gel column(MeOH in DCM from 1% to 10%) to provide 23-3 (13.1 g, 92.5%) as a whitefoam solid.

To a stirred solution of 23-3 (12.0 g, 53 mmol) in anhydrous CH₃CN wasadded TEA.3HF (8.5 g, 53 mmol) and NIS (10.2 g, 63.6 mmol) at 0° C. Themixture was stirred for 30 mins, and slowly warmed to R.T. The mixturewas stirred for another 30 mins. The solid was removed by filtration,and washed with DCM to give 23-4 (14 g, 73%) as a yellow solid. ESI-MS:m/z 373.0 [M+H]⁺.

To a stirred solution of 23-4 (12.0 g, 32 mmol) and DMAP (1.2 g, 9.6mmol) in pyridine (100 mL) was added Bz₂O (21.7 g, 96 mmol) at R.T. Themixture was stirred at 50° C. for 16 h. The resulting solution wasquenched with water, and concentrated to dryness at low pressure. Thecrude was purified on silica gel column (50% EA in PE) to give 23-5 (15g, 81%) as a white solid. ESI-TOF-MS: m/z 581.0 [M+H]⁺.

Tetra-butylammonium hydroxide (288 mL as 54-56% aqueous solution, 576mmol) was adjusted to pH-4 by adding TFA (48 mL). The resulting solutionwas treated with a solution of 23-5 (14 g, 24 mmol) in DCM (200 mL).m-Cloroperbenzoic acid (30 g, 60-70%, 120 mmol) was added portion wisewith vigorous stirring, and the mixture was stirred overnight. Theorganic layer was separated and washed with brine. The resultingsolution was dried over magnesium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography to give 23-6(7.5 g, 68%)

Compound 23-6 (5.0 g, 10.6 mmol) was treated with 7N NH₃.MeOH (100 mL),and the mixture was stirred for 5 h. The mixture was then concentratedto dryness at low pressure. The residue was washed with DCM, and thesolid was filtered to give 23-7 (2.1 g, 75%) as a white foam. ESI-MS:m/z 263.0 [M+H]⁺.

To a solution of 23-7 (2.1 g, 8.0 mmol) in pyridine was added TIDPSCl(2.5 g, 8.0 mmol) dropwise at 0° C., and stirred for 12 h. at R.T. Thesolution was quenched with water, and concentrated to dryness at lowpressure. The crude was purified by column chromatography (EA in PE from10% to 50%) to give pure 23-8 (1.6 g, 40%) as a white foam.

A solution of 23-8 (1.5 g, 3.0 mmol) and IBX (1.69 g, 6.0 mmol) inanhydrous CH₃CN (10 mL) was stirred at 80° C. for 3 h. The mixture wascooled down to R.T. and filtered. The filtrate was concentrated todryness at low pressure. The residue was purified by columnchromatography (EA in PE from 2% to 50%) to give pure 23-9 (1.2 g, 80%)as a white foam. ESI-MS: m/z 503.0 [M+H]⁺.

Compound 23-9 (500 mg, 1 mmol) was dissolved in dry THF (8 mL). Ethynylmagnesium bromide (8 mL of 0.5M solution in cyclohexane) was added atR.T. After 30 mins, additional ethynyl magnesium bromide (8 mL) wasadded. The mixture was left for 30 mins, and then quenched with sat.solution of ammonium chloride. The product was extracted with EA. Theorganic extracts were washed with brine, dried, and concentrated. Theresidue was purified by flash chromatography on silica gel in EA toremove the dark color. The yellow compound was dissolved in THF (3 mL)and treated with TBAF (1 mL, 2M solution in THF) for 30 mins. Thesolvent was evaporated, and the residue was subjected to silica gelchromatography on a Biotage cartridge (25 g). EA saturated with waterwas used for isocratic elution. Each fractions were analyzed by TLC inDCM-MeOH (9:1 v/v). Fractions containing only the isomer with a high Rfwere concentrated to give pure compound 23 (110 mg). MS: 285.1 [M−1]⁻.

Example 8 Compound 22

Compound 23 (57 mg, 0.2 mmol) was dissolved in CH₃CN (2 mL), containingN-methylimidazole (40 uL). The phosphorochloridate (207 mg, 0.6 mmol)was added, and the mixture was kept overnight at 40° C. The mixture wasdistributed between water and EA. The organic layer was separated,washed with brine, dried and evaporated. The product was isolated bysilica gel chromatography in gradient of methanol in DCM from 0% to 15%.Compound 22 was obtained (46 mg, 39%). MS: m/z 593.9 [M−1]⁻.

Example 9 Compound 51

To a solution of triethylammoniumbis(isopropyloxycarbonyloxymethyl)phosphate (0.74 mmol) in THF was added51-1 (0.16 gg; 0.49 mmol). The mixture evaporated and rendered anhydrousby coevaporating with pyridine follow by toluene. The residue wasdissolved in anhydrous THF and cooled in an ice-bath. Diisopropylethylamine (0.34 mL) was added, followed by BOP-Cl (250 mg) and3-nitro-1,2,4-triazole (112 mg) in THF (5 mL). The mixture was stirredat 0° C. for 90 mins, diluted with EtOAc, washed with sat. aq. NaHCO₃and brine, and dried (Na₂SO₄). The residue was purified on silica columnwith 3-10% i-PrOH in DCM to give 51-2 (0.2 g, 64%).

A solution of 51-2 (0.20 g; 0.31 mmol) in 80% aq. HCOOH was stirred atR.T. for 2 h, and then concentrated. The residue was coevaporated withtoluene and then with MeOH containing a small amount of Et₃N (2 drops).Purification on silica gel (10 g column) with CH₂Cl₂/MeOH (4-10%gradient) was followed by RP-HPLC purification in 5 runs on a SynergiHydro RP column 250×30 mm (Phenomenex P/N 00G-4375-U0-AX) using H₂O andACN both 50 mM TEAA. The Gradient was 25-75% ACN in 20 mins at 24mL/mins, 254 nM detection. The compound eluted at 16.0 minutes; and thepure fractions were pooled and lyophilized. TEAA was removed bydissolving the compound in DMSO (2 mL) and using the same column andsame gradient, using only H₂O and ACN. Pure fractions were pooled andlyophilized to give compound 51 (18 mg). MS: m/z=1197 [2M+1]⁺.

Example 10 Compound 8

Compound 8-1 (5.0 g, 8.5 mmol) and 2-amino-6-chloropurine (3.0 g, 17.7mmol) were co-concentrated with anhydrous toluene for 3 times. To astirred suspension of the above mixtures in anhydrous MeCN (50 mL) wasadded DBU (7.5 g, 49 mmol) at 0° C. The mixture was stirred at 0° C. for15 mins, and then TMSOTf (15 g, 67.6 mmol) was added dropwise at 0° C.The mixture was stirred at 0° C. for 15 mins. The mixture was heated at70° C. overnight. The mixture was cooled to R.T., and diluted with EA(100 mL). The solution was washed with sat. NaHCO₃ solution and brine.The organic layer was dried over Na₂SO₄ and concentrated at lowpressure. The residue was purified by column on silica gel (PE/EA: from15/1 to 3/1) to give 8-2 (2.5 g, 46.3%) as a white foam.

To a solution of 8-2 (10 g, 15.7 mmol), AgNO₃ (8.0 g, 47 mmol) andcollidine (10 mL) in anhydrous DCM (20 mL) was added MMTrCl (14.5 g, 47mmol) in small portions under N₂. The mixture was stirred at R.T.overnight. The mixture was filtered, and the filtrate was washed withsat. aq. NaHCO₃ and brine. The organic layer was dried over anhydrousNa₂SO₄, and concentrated at low pressure. The residue was purified bysilica gel column (PE/ME=20/1 to 8/1) to give 8-3 (10 g, 70%) as ayellow solid.

To a solution of 3-hydroxy-propionitrile (3.51 g, 49.4 mmol) inanhydrous THF (100 mL) was added NaH (2.8 g, 70 mmol) at 0° C., and themixture was stirred at R.T. for 30 mins. A solution of 8-3 (8.5 g, 9.35mmol) in anhydrous THF (100 mL) at 0° C. was added, and the mixture wasstirred at R.T. overnight. The reaction was quenched with water, andextracted with EA (100 mL). The organic layer was dried over anhydrousNa₂SO₄, and concentrated at low pressure. The residue was purified bysilica gel column (DCM/MeOH=100/1 to 20/1) to give 8-4 (4.5 g, 83%) as awhite solid.

Compound 8-4 (1.5 g, 2.6 mmol) was co-concentrated with anhydrouspyridine 3 times. To an ice-cooled solution of 8-4 in anhydrous pyridine(30 mL) was added TsCl (1.086 g, 5.7 mmol), and the mixture was stirredat 0° C. for 1 h. The reaction was quenched with water, and extractedwith EA (80 mL). The organic layer was dried over anhydrous Na₂SO₄, andconcentrated at low pressure. The residue was purified by silica gelcolumn (DCM/MeOH=100/1 to 15/1) to give 8-5 (1.4 g, 73%) as a whitesolid.

To a solution of 8-5 (4.22 g, 5.7 mmol) in acetone (60 mL) was added NaI(3.45 g, 23 mmol), and the mixture was refluxed overnight. The reactionwas quenched with sat. aq. Na₂S₂O₃ and extracted with EA (100 mL). Theorganic layer was dried over anhydrous Na₂SO₄, and concentrated at lowpressure. The residue was purified by silica gel column (DCM/MeOH=100/1to 15/1) to give 8-6 (4 g, 73%) as a white solid.

To a solution of 8-6 (4.0 g, 5.8 mmol) in anhydrous THF (60 mL) wasadded DBU (3.67 g, 24 mmol), and the mixture was stirred at 60° C.overnight. The mixture was diluted with EA (80 mL), and the solution waswashed with brine. The organic layer was dried over anhydrous Na₂SO₄,and concentrated at low pressure. The residue was purified by silica gelcolumn (DCM/MeOH=100/1 to 20/1) to give 8-7 (2 g, 61%) as a white solid.

To an ice-cooled solution of 8-7 (500 mg, 0.89 mmol) in anhydrous DCM(20 mL) was added AgF (618 mg, 4.9 mmol) and a solution of I₂ (500 mg,1.97 mmol) in anhydrous DCM (20 mL). The mixture was stirred at R.T. for3 h. The reaction was quenched with sat Na₂S₂O₃ and NaHCO₃ aqueous, andthe mixture was extracted with DCM (50 mL). The organic layer wasseparated, dried over anhydrous Na₂SO₄, and concentrated to give thecrude 8-8 (250 mg) as a yellow solid.

To a solution of crude 8-8 (900 mg, 1.28 mmol) in anhydrous DCM (50 mL)was added DMAP (1.0 g, 8.2 mmol) and BzCl (795 mg, 5.66 mmol). Themixture was stirred at R.T. overnight. The mixture was washed with sat.aq. NaHCO₃ and brine. The organic layer was dried over anhydrous Na₂SO₄,and concentrated at low pressure. The residue was purified by prep-TLC(DCM/MeOH=15:1) to give 8-9 (300 mg, 26%) as a white solid.

To a solution of crude 8-9 (750 mg, 0.82 mmol) in anhydrous HMPA (20 mL)was added NaOBz (1.2 g, 8.3 mmol) and 15-crown-5 (1.8 g, 8.3 mmol). Themixture was stirred at 60° C. for 2 d. The mixture was diluted with EA,and the solution was washed with brine. The organic layer was dried overanhydrous Na₂SO₄, and concentrated at low pressure. The residue waspurified by prep-TLC (PE/EA=1:1) to give crude 8-10 (550 mg, 73%) as awhite solid.

The crude 8-10 (550 mg, 0.6 mmol) was dissolved in NH₃/MeOH (7N, 50 mL).The mixture was stirred at R.T. overnight. The mixture was concentrated,and the residue was purified by silica gel column (DCM/MeOH from 100/1to 20/1) to give 8-11 (62 mg, 17%) as a white solid. ESI-MS: m/z 598.0[M+H]⁺.

A solution of 8-11 (12 mg) in 80% formic acid (0.5 mL) stood at R.T. for3.5 h and then was concentrated. The residue was co-evaporated withMeOH/toluene 4 times in a vial, and triturated with EtOAc at 40° C. TheEtOAc solution removed with pippet. The trituration step was repeatedseveral times, and the remaining solid was dissolved in MeOH. Thesolution was concentrated and dried to give compound 8 as off whitesolid (4.7 mg). ESI-MS: m/z 326.6 [M+H]⁺.

Example 11 Compounds 34 and 35

To a stirred suspension of 8-1 (50 g, 84.8 mmol) and2-amino-6-chloropurine (28.6 g, 169.2 mmol) in anhydrous MeCN (500 mL)was added DBU (77.8 g, 508 mmol) at 0° C. The mixture was stirred at 0°C. for 30 mins, and TMSOTf (150.5 g, 678 mmol) was added dropwise at 0°C. The mixture was stirred at R.T. for 20 mins until a clear solutionwas formed. The mixture was stirred at 90-110° C. overnight. The mixturewas cooled to R.T., and diluted with EA. The solution was washed withsat. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄and then concentrated at low pressure. The residue was purified bysilica gel column (PE/EA=2/1) to give 34-1 (30 g, 55.5%) as a whitesolid.

To a solution of 34-1 (30 g, 47.1 mmol) in anhydrous DCM (300 mL) wasadded collidine (30 mL), AgNO₃ (24 g, 141.4 mmol) and MMTrCl (43.6 g,141.4 mmol). The mixture was stirred at R.T. overnight. The mixture wasfiltered, and the filtrate was washed with water and brine. The organiclayer was dried over anhydrous Na₂SO₄, and concentrated at low pressure.The residue was purified by silica gel column (PE/EA=4/1) to give 34-2(35 g, 82%) as a white solid.

To a stirred solution of 34-2 (35 g, 38.5 mmol) in anhydrous EtOH (150mL) was added a solution of EtONa in EtOH (2N, 150 mL). The mixture wasstirred at R.T. overnight, and then concentrated at low pressure. Theresidue was dissolved in EA (200 mL) and the solution was washed withwater and brine. The organic layer was dried over Na₂SO₄, andconcentrated at low pressure. The residue was purified by silica gelcolumn (DCM/MeOH=100/2) to give 34-3 (19 g, 81%) as a white solid.

Compound 34-3 (19 g, 31.3 mmol) was co-concentrated with anhydrouspyridine for 3 times. To an ice-cooled solution of 34-3 in anhydrouspyridine (120 mL) was added a solution of TsCl (6.6 g, 34.6 mmol) inpyridine (40 mL) dropwise at 0° C. The mixture was stirred at 0° C. for16 h. The mixture was quenched with water, and the reaction mixture wasconcentrated. The residue was re-dissolved in EA (200 mL). The solutionwas washed with sat. aq. NaHCO₃ and brine. The organic layer was driedover anhydrous Na₂SO₄ and filtered, and the filtrate was concentrated.The residue was purified by silica gel column (DCM/MeOH=100/1) to give34-4 (16 g, 67%) as a yellow solid.

To a solution of 34-4 (15 g, 19.7 mmol) in acetone (100 mL) was addedNaI (30 g, 197 mmol). The mixture was refluxed overnight, and thenconcentrated at low pressure. The residue was purified by silica gelcolumn (DCM/MeOH=100/1) to give 34-5 (9 g, 63.7%) as a white solid.

To a solution of 34-5 (8 g, 11.2 mmol) in anhydrous THF (60 mL) wasadded DBU (5.12 g, 33.5 mmol), and the mixture was heated at 60° C.overnight. The mixture was diluted with EA, and washed with water andbrine. The organic layer was dried over anhydrous Na₂SO₄ and filtered,and the filtrate was concentrated. The residue was purified by silicagel column (PE/acetone=4/1) to give 34-6 (5.7 g, 86%) as a white solid.¹H-NMR (CD₃OH, 400 MHz) δ=8.18 (s, 1H), 7.17-7.33 (m, 12H), 6.80 (d,J=8.8 Hz, 2H), 5.98 (s, 1H), 5.40 (d, J=8.6 Hz, 1H), 3.87 (m, 5H), 3.75(s, 3H), 2.69 (s, 1H), 1.05 (s, 3H).

To an ice-cooled solution of 34-6 (4.44 g, 7.5 mmol) in anhydrous MeCN(45 mL) was added TEA.3HF (1.23 g, 7.6 mmol) and NIS (2.16 g, 9.5 mmol).The mixture was stirred at R.T. for 2-3 h. The reaction was quenchedwith sat. Na₂SO₃ and NaHCO₃ solution. The mixture was extracted with EA(3×100 mL). The organic layer was separated, dried over anhydrous Na₂SO₄and concentrated at low pressure. The residue was purified by silica gelcolumn (DCM/acetone=100/2) to give 34-7 (4.4 g, 79.8%) as a white solid.

To a solution of 34-7 (5.36 g, 7.3 mmol) in anhydrous DCM (50 mL) wasadded DMAP (3.6 g, 29.8 mmol) and BzCl (3.1 g, 22.1 mmol) at 0° C. Themixture was stirred at R.T. overnight. The mixture was washed with sat.aq. NaHCO₃ and brine. The organic layer was concentrated, and theresidue was purified by silica gel column (PE/EA=5/1) to give 34-8 (5.6g, 81.3%) as a white solid.

To a solution of 34-8 (5.0 g, 5.3 mmol) in anhydrous DMF (150 mL) wasadded NaOBz (7.64 g, 53 mmol) and 15-crown-5 (14 g, 68 mmol). Themixture was stirred at 90-100° C. for 48 h. The mixture was diluted withEA, and washed with water and brine. The organic layer was concentrated,and the residue was purified by silica gel column (PE/EA=5/1) to give34-9 (3.9 g, 78.5%) as a white solid.

Compound 34-9 in NH₃ in MeOH (7N, 60 mL) was stirred at R.T. for 18 h.The mixture was concentrated at low pressure. The residue was purifiedby silica gel column (DCM/acetone=50/1) to give 34-10 (500 mg, 74.7%) asa white solid. ESI-MS: m/z 626.3 [M+H]⁺.

To a solution of 34-10 (350 mg, 0.56 mmol) in anhydrous pyridine (4 mL)was added imidazole (50 mg, 0.72 mmol) and TBSCl (108 mg, 0.72 mmol) at0 to 5° C., and stirred at R.T. for 15 h. The reaction was quenched withabsolute EtOH (0.5 mL). The solution was concentrated to dryness underreduced pressure. The residue was dissolved in EA (150 mL), and washedwith water, sat. NaHCO₃ and brine. The combined organic layers weredried over Na₂SO₄, filtered and evaporated at low pressure. The residuewas purified by silica gel column (10-30% EA in hexanes) to give 34-11(338 mg, 81.8%) as a white solid.

To a solution of compound 34-11 (328 mg, 0.44 mmol), AgNO₃ (226 mg, 1.33mmol) and collidine (0.59 mL, 4.84 mmol) in anhydrous DCM (4 mL) wasadded MMTrCl (410 mg, 1.33 mmol) under N₂. The mixture was stirred atR.T. overnight under N₂, and monitored by TLC to completion. The mixturewas filtered through pre-packed Celite filter, and the filtrate waswashed with water, 50% aqueous citric acid, and brine. The organic layerwas separated, dried over anhydrous Na₂SO₄, filtered and concentrated atlow pressure. The residue was purified by silica gel column (EA inhexanes from 0% to 30%) to give 34-12 (337 mg).

To a solution of 34-12 (337 mg, 0.33 mmol) in anhydrous THF (4 mL) wasadded 1.0 M solution of TBAF (0.66 ML, 0.66 mmol) at 0 to 5° C. Thereaction was slowly warmed to R.T., and stirred for 1 h. The mixture wasquenched with silica gel, and filtered. The solvents were evaporated togive the crude product, which was purified by silica gel column (EA inhexanes from 0% to 50%) to give 34-13 (188 mg).

To a stirred solution of 34-13 (180 mg, 0.16 mmol) in anhydrous CH₃CN(2.5 mL) was added N-methylimidazole (132 μL, 1.6 mmol) at 0-5° C.(ice/water bath) followed by solution of phenyl(cyclohexanoxy-L-alaninyl) phosphorochloridate (207 mg, 0.6 mmol,dissolved in 2 mL of CH₃CN). The solution was stirred at R.T. for 2.5 h,and the mixture was diluted with EA followed by addition of water (15mL). The solution was washed H₂O, 50% aqueous citric acid solution andbrine. The organic layer was separated, dried over anhydrous MgSO₄ andfiltered. The filtrate was concentrated in vacuum to give a residue,which was purified on silica gel with 0 to 40% EA/hexanes to give 34-14(75.8 mg) and 34-15 (108 mg) as a slower eluting isomer.

Compound 34-14 (76 mg, 0.063 mmol) was dissolved in anhydrous CH₃CN (0.5mL), and 4N HCl in dioxane (47 μL) was added at 0 to 5° C. (ice/waterbath). The mixture was stirred at R.T. for 40 mins, and anhydrous EtOH(200 μL) was added. The solvents were evaporated at R.T. andco-evaporated with toluene 3 times. The residue was dissolved in 50%CH₃CN/H₂O, purified on a reverse-phase HPLC (C18) using acetonitrile andwater, and lyophilized to give compound 34 (26.6 mg). ESI-LCMS:m/z=663.3 [M+H]⁺.

Compound 34-15 (108 mg, 0.089 mmol) was dissolved in anhydrous CH₃CN(0.7 mL), and 4N HCl in dioxane (67 μL) was added at 0 to 5° C.(ice/water bath). The mixture was stirred at R.T. for 60 mins, andanhydrous EtOH (200 μL) was added. The solvents were evaporated at R.T.and co-evaporated with toluene 3 times. The residue was dissolved in 50%CH₃CN/H₂O, purified on a reverse-phase HPLC (C18) using acetonitrile andwater, and lyophilized to give compound 35 (40.3 mg). ESI-LCMS:m/z=663.2 [M+H]⁺.

Example 12 Compound 25

To a solution of 25-1 (260 mg, 1 mmol), PPh₃ (780 mg, 3 mmol) andpyridine (0.5 mL) in anhydrous THF (8 mL) were added I₂ (504 mg, 2 mmol)at R.T., and the mixture was stirred at R.T. for 12 h. The mixture wasdiluted with EtOAc and washed with 1M HCl solution. The organic layerwas dried over Na₂SO₄, filtered and concentrated at low pressure. Theresidue was purified by silica gel column (5% MeOH in DCM) to give 25-2(190 mg, 85%) as a white solid.

To a solution of 25-2 (190 mg, 0.52 mmol) in THF (4 mL) was added DBU(760 mg, 5 mmol) at R.T., and the mixture was heated at 50° C.overnight. The mixture was diluted with EtOAc, and washed with water.The organic layer was dried over anhydrous Na₂SO₄ and concentrated atlow pressure. The residue was purified by silica gel column (30% EA inPE) to give 25-3 (75 mg, 52%) as a white solid.

To a solution of 25-3 (200 mg, 0.82 mmol) in MeCN (anhydrous, 4 mL) wasadded NIS (337 mg, 1.5 mmol) and TEA.3HF (213 mg, 1.25 mmol) at R.T.,and the mixture was stirred at R.T. for 7 h. The reaction was quenchedwith sat. Na₂SO₃ solution and sat. aq. NaHCO₃ solution. The mixture wasextracted with EA. The organic layer was separated, dried over anhydrousNa₂SO₄, and concentrated at low pressure. The residue was purified bysilica gel column (20% EA in PE) to give 25-4 (300 mg, 62%) as a whitesolid.

To a solution of 25-4 (194 mg, 0.5 mmol) in pyridine (5 mL) was addedBzCl (92 mg, 0.55 mmol) at 0° C. The mixture was stirred at R.T. for 5h, and the reaction was quenched with water. The mixture wasconcentrated at low pressure, and the residue was purified by silica gelcolumn (20% EA in PE) to give 25-5 (397 mg, 81%) as a white solid.

To a solution of 25-5 (1.05 g, 2.13 mmol) in DCM (12 mL) was added amixture of TFA (0.5 mL) and Bu₄NOH (1 mL), followed by addition ofm-CPBA (1.3 g, 6 mmol) at R.T. The mixture was stirred at R.T. for 5 h.The mixture was washed with sat. Na₂SO₃ solution and aq. NaHCO₃solution. The organic layer was dried over anhydrous Na₂SO₄, andconcentrated at low pressure. The residue was purified by silica gelcolumn (30% EA in PE) to give 25-6 (450 mg, 63%) as a white solid.

Compound 25-6 (250 mg, 0.65 mmol) was dissolved in NH₃/MeOH (5 mL). Themixture was stirred at R.T. for 5 h, and then concentrated at lowpressure. The residue was purified by silica gel column (5% MeOH in DCM)to give compound 25 (120 mg, 66%) as a white powder. ESI-MS: m/z 279.0[M+H]⁺.

Example 13 Compound 31

To a stirred solution of compound 25 (100 mg, 0.36 mmol) in anhydrousTHF (3.0 mL) was added N-methylimidazole (236 μL, 2.87 mmol) at 0° C.(dry ice/acetone bath) followed by a solution of the phosphorochloridate(329 mg, 1.08 mmol, dissolved in 2 mL of THF). The solution was stirredat 0° C. for 1 h, the reaction temperature was raised up-to 10° C.during the next 1 h, and the solution was left at 10° C. for the next 4h. The mixture was cooled to 0 to 5° C., diluted with EA, and water wasadded (15 mL). The solution was washed H₂O, 50% aqueous citric acidsolution and brine. The organic layer was separated, dried overanhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuum togive a residue, which dissolved in 25% CH₃CN/H₂O. The residue waspurified on a reverse-phase HPLC (C18) using acetonitrile and water,followed by lyophilization to give a mixture of two isomers of compound31 (17.5 mg). MS: m/z 546.05 [M−H]⁻.

Example 14 Compound 27

To a solution of compound 25 (139 mg, 0.5 mmol) in pyridine (5 mL) wasadded BzCl (92 mg, 0.55 mmol) at 0° C. The mixture was stirred at R.T.for 5 h, diluted with EtOAc and washed with 1N HCl solution. The organiclayer was dried over anhydrous Na₂SO₄, and concentrated at low pressure.The residue was purified by silica gel column (20% EA in PE) to give27-1 (274 mg, 79%) as a white solid.

To a solution of 27-1 (490 mg, 1 mmol), DMAP (244 mg, 2 mmol) and TEA(205 mg, 2.1 mmol) in MeCN (10 mL) were added TPSCl (604 mg, 2 mmol) at0° C. The mixture was stirred at R.T. for 2 h., and then NH₄OH aq. wasadded at R.T. The mixture was stirred for 0.5 h, diluted with EtOAc andwashed with sat. aq. NaHCO₃ and brine. The organic layer was dried overanhydrous Na₂SO₄, and concentrated at low pressure. The residue waspurified by silica gel column (30% EA in PE) to give 27-2 (250 mg, 41%)as a white solid.

Compound 27-2 (250 mg, 0.51 mmol) was dissolved in NH₃/MeOH (15 mL). Themixture was stirred at R.T. for 5 h. and then concentrated at lowpressure. The residue was purified by silica gel column (5% DCM in DCM)to give compound 27 (95 mg, 66%) as a white powder. ESI-MS: m/z 278.1[M+H]⁺.

Example 15 Compound 29

To a solution of compound 29-1 (30 g, 0.08 mol) in anhydrous THF (300mL) was added a solution of lithium tri-tert-butoxyaluminohydride (120mL, 0.12 mol) dropwise at −78° C. under N₂. The mixture was stirred at−20° C. for 1 h. The reaction was quenched with sat. aq. NH₄Cl and thenfiltered. The filtrate was extracted with EA (3×300 mL). The organiclayer was dried over anhydrous Na₂SO₄, and concentrated at low pressure.The residue was purified by silica gel column (10% EA in PE) to give29-2 (26 g, 86%) as a colorless oil.

To a stirred solution of PPh₃ (37.7 g, 0.144 mol) in DCM (100 mL) wasadded compound 29-2 (27 g, 0.072 mol) at −20° C. under N₂. After themixture was stirred at R.T. for 15 mins, CBr₄ (42 g, 0.129 mol) wasadded while maintaining the reaction temperature between −25 and −20° C.under N₂. The mixture was then stirred below −17° C. for 20 mins. Silicagel was added into the solution, and then purified by flash silica gelcolumn separation to give the crude oil product. The crude was purifiedby silica gel column (EA in PE from 2% to 20%) to give 29-3 (a-isomer,17 g, 55%) as a colorless oil.

A mixture of 6-Cl-guanine (11.6 g, 68.8 mmol) and t-BuOK (8.2 g, 73mmol) in t-BuOH (200 mL) and MeCN (150 mL) was stirred at 35° C. for 30mins, and then 29-3 (10 g, 22.9 mmol) in MeCN 100 mL) was added at R.T.The mixture was heated at 50° C. overnight. The reaction was quenchedwith a solution of NH₄Cl (5 g) in water (40 mL), and the mixture wasfiltered. The filtrate was evaporated at low pressure. The residue waspurified by silica gel column (20% EA in PE) to give 29-4 (6 g, 42%) asa yellow solid.

To a solution of 29-4 (12.5 g, 23.8 mol) in DCM (50 mL) was added AgNO₃(8.1 g, 47.6 mmol), collidine (5.77 g, 47.6 mmol) and MMTrCl (11 g, 35.7mmol). The mixture was stirred at R.T. overnight. The reaction wasquenched with MeOH (5 mL), filtered and concentrated at low pressure.The residue was purified by silica gel column (5% MeOH in DCM) to givethe intermediate (16 g, 86%) as a yellow solid. To a solution ofHOCH₂CH₂CN (4.7 g, 66 mmol) in THF (200 mL) was added NaH (3.7 g, 92mmol) at 0° C. The mixture was stirred at R.T. for 30 mins. A solutionof the intermediate (10.5 g, 13 mmol) in THF (50 mL) was added, and thereaction mixture was stirred at R.T. for 12 h. The reaction was quenchedwith MeOH (2 mL), diluted with EA (100 mL), and washed with brine. Theorganic layer was dried over anhydrous Na₂SO₄, and concentrated at lowpressure. The residue was purified by silica gel column (5% MeOH in DCM)to give 29-5 (5.8 g, 77%) as a yellow solid.

To a solution of PPh₃ (7.0 g, 26.6 mmol) in anhydrous pyridine (100 mL)was added I₂ (6.3 g, 24.9 mmol), and stirred at R.T. for 30 mins. Themixture was treated with a solution of 29-5 (9.5 g, 16.6 mmol) inpyridine (40 mL). The mixture was stirred at R.T. overnight. Thereaction was quenched with sat. Na₂S₂O₃ solution, and the mixture wasextracted with EA. The organic layer was washed with brine, dried overanhydrous Na₂SO₄, and concentrated at low pressure. The residue waspurified by silica gel column (30% EA in PE) to give 29-6 (7 g, 66%) asa yellow solid.

To a solution of 29-6 (7.5 g, 11 mmol) in dry THF (50 mL) was added DBU(5.4 g, 33 mmol), and the mixture was heated to reflux for 4 h. Themixture was diluted with EA (3×100 mL), and washed with brine. Theorganic layer was dried over anhydrous Na₂SO₄, and concentrated at lowpressure. The residue was purified by silica gel column (30% EA in PE)to give 29-7 (4.0 g, 67%) as a white solid.

To an ice-cooled solution of 29-7 (3.0 g, 5.4 mmol) in anhydrous MeCN(20 mL) was added TEA.3HF (0.65 g, 4.1 mmol) and NIS (1.53 g, 6.78 mmol)at R.T., and the reaction mixture was stirred at R.T. for 2 h. Themixture was diluted with EA (50 mL), and washed with sat. Na₂S₂O₃solution and NaHCO₃ aq. The organic layer was dried over anhydrousNa₂SO₄, and concentrated to dryness at low pressure. The residue waspurified by prep-HPLC (0.1% HCOOH in water and MeCN) to separate the twoisomers (about 1:1). NOE showed the polar one was 29-8 (0.6 g, 16%) as awhite solid.

To a solution of 29-8 (0.7 g, 1 mmol) in dry pyridine (10 mL) was addedBzCl (147 mg, 1.05 mmol) at 0° C. The mixture was stirred at R.T. for 3h. The mixture was then diluted with EA, and washed with sat. NaHCO₃ aq.and brine. The organic layer was dried over Na₂SO₄, and evaporated atlow pressure. The residue was purified by silica gel column (20% EA inPE) to give 29-9 (0.65 g, 81%) as a white solid.

To a solution of 29-9 (0.65 g, 0.8 mmol) in dry DMF (40 mL) was addedNaOBz (1.15 g, 8 mmol) and 15-crown-5 (1.77 g, 8 mmol). The mixture wasstirred at 100° C. for 48 h. The solvent was evaporated at low pressure,and the residue was dissolved in EA (30 mL), and washed with water andbrine. The organic layer was dried over Na₂SO₄ and concentrated at lowpressure. The residue was purified by silica gel column (20% EA in PE)to give 29-10 (500 mg, 78%) as a white solid.

Compound 29-10 (400 mg, 0.5 mmol) in NH₃/MeOH (7N, 100 mL) was stirredat R.T. for 18 h. The mixture was concentrated at low pressure, and theresidue was purified by silica gel column (5% MeOH in DCM) to give 29-11(220 mg, 63%) as a white solid. ESI-MS: m/z 590.3 [M+H]⁺.

Compound 29-11 (59 mg, 0.1 mmol) was dissolved in 50% TFA in methanol(10 mL), and the mixture was kept at R.T. for 2 h. The solvent wasevaporated and co-evaporated with a methanol/toluene mixture to removetraces of the acid. The residue was suspended in CH₃CN (1 mL) andcentrifuged. The precipitate was washed with CH₃CN (1 mL) and dried.Compound 29 was obtained as a colorless solid (21 mg, 65%. MS: m/z 316.2[M−1]⁻.

Example 16 Compounds 42 and 43

A freshly prepared EtONa in dry EtOH (2N, 150 mL) was added to asolution of 29-4 (13.67 g, 17.15 mmol) in EtOH (50 mL) at 0° C. Themixture was stirred at R.T. for 1 h, and then concentrated at lowpressure. The residue was purified by silica gel column (5% MeOH in DCM)to give 42-1 (10 g, 98%) as a yellow solid.

To a solution of PPh₃ (2.73 g, 10.4 mol) in anhydrous pyridine (60 mL)was added I₂ (2.48 g, 9.76 mmol) at R.T., and the reaction mixture wasstirred R.T. for 30 mins. A solution of 42-1 (3.9 g, 6.51 mmol) inpyridine (10 mL) was added. The mixture was stirred at R.T. overnight.The reaction was quenched with sat. Na₂S₂O₃ solution and NaHCO₃ aq., andthen extracted with EA (100 mL). The organic layer was dried overanhydrous Na₂SO₄, and evaporated at low pressure. The residue waspurified by silica gel column (2% MeOH in DCM) to give 42-2 (3.0 g, 75%)as a yellowed solid.

To a solution of 42-2 in dry THF (300 mL) was added DBU (14.0 g, 91.8mmol), and the mixture was heated to reflux for 3 h. The mixture wasconcentrated at low pressure. The residue was dissolved in EA (100 mL),and washed with brine. The organic layer was dried over anhydrousNa₂SO₄, and evaporated at low pressure. The residue was purified bysilica gel column (20% EA in PE) to give 42-3 (0.6 g, 37.5%) as a whitesolid.

To an ice-cooled solution of 42-3 (2.0 g, 3.44 mmol) in anhydrous MeCN(20 mL) was added NIS (0.975 g, 4.3 mmol) and TEA.3HF (0.82 g, 5.16mmol) at 0° C. The mixture was stirred at R.T. for 2 h. The reaction wasquenched with sat. Na₂SO₃ and NaHCO₃ aqueous solution, and thenconcentrated at low pressure. The residue was dissolved in EA (50 mL),washed with brine, dried over anhydrous Na₂SO₄, and evaporated at lowpressure. The residue was purified by silica gel column (20% EA in PE)to give 42-4 (1.5 g, 60%) as a white solid.

To a solution of 42-4 (1 g, 1.37 mmol) in dry pyridine (100 mL) wasadded BzCl (0.23 g, 1.65 mmol) at 0° C. The reaction was stirred for 30mins and checked by LCMS. The mixture was concentrated at low pressure,and the residue was dissolved in EA (50 mL). The solution was washedwith brine. The organic layer was dried over MgSO₄, and evaporated atlow pressure. The residue was purified by silica gel columnchromatography (10% EA in PE) to give 42-5 (0.9 g, 78%) as a whitesolid.

To a solution of 42-5 (2 g, 2.4 mmol) in dry DMF (40 mL) was added NaOBz(3.46 g, 24 mmol) and 15-crown-5 (4.5 mL). The mixture was stirred at95° C. for 72 h. The mixture was then diluted with EA (100 mL), andwashed with water and brine. The organic phase was dried over MgSO₄, andconcentrated at low pressure. The residue was purified by silica gelcolumn (15% EA in PE) to give 42-6 (1.5 g, 75%) as a white solid.

Compound 42-6 (1.35 g, 1.64 mmol) in NH₃/MeOH (150 mL) was stirred atR.T. for 18 h. The mixture was concentrated at low pressure, and theresidue was purified by silica gel column (5% MeOH in DCM) to give 42-7(0.9 g, 90%) as a white solid. ESI-MS: m/z 618.3 [M+H]⁺.

To a solution of 42-7 (99 mg, 0.16 mmol) in DCM (1.0 mL), triethylamine(92.7 μL, 0.64 mmol) was added at R.T. The mixture was cooled to 0 to 5°C. (ice/water bath), and freshly prepared and distilled isopropylphosphorodichloridate (36.6 μL, 0.2 mmol, prepared according to aprocedure, Reddy et al. J. Org. Chem. 2011, 76 (10), 3782-3790) wasadded to the mixture. The mixture was stirred 0 to 5° C. (ice/waterbath) for 15 mins, followed by addition of N-methylimidazole (26.3 μL,0.32 mmol). The mixture was then stirred for 1 h at 0 to 5° C. TLCshowed absence of 42-7. EA (100 mL) was added, followed by water. Theorganic layer was washed H₂O, saturated aqueous NH₄Cl solution andbrine. The organic layer was separated, dried over anhydrous MgSO₄ andfiltered. The filtrate was concentrated in vacuum to give a residue,which was purified on silica gel with 0 to 10% iPrOH/DCM to give amixture of 42-a and 42-b (61.5 mg).

A mixture of 42-a and 42-b (61.5 mg, 0.085 mmol) was dissolved inanhydrous CH₃CN (0.5 mL), and 4N HCl in dioxane (64 μL) was added at 0to 5° C. (ice/water bath). The mixture was stirred at R.T. for 40 mins,and anhydrous EtOH (200 μL) was added. The solvents were evaporated atR.T. and co-evaporated with toluene 3 times. The residue was dissolvedin 50% CH₃CN/H₂O, was purified on a reverse-phase HPLC (C18) usingacetonitrile and water, followed by lyophilization to give compound 42(1.8 mg) and compound 43 (14.5 mg).

Compound 42: ¹H NMR (CD₃OD-d₄, 400 MHz) δ 8.0 (s, 1H), 6.69 (d, J=16.0Hz, 1H), 5.9-5.6 (br s, 1H), 4.94-4.85 (m, 1H), 4.68-4.52 (m, 3H),1.49-1.3 (m, 12H); ¹⁹F NMR (CD₃OD-d₄) δ −122.8 (s), −160.06 (s); ³¹P NMR(CD₃OD-d₄) 6-7.97 (s). ESI-LCMS: m/z=450.1 [M+H]⁺; Compound 43: ¹H NMR(CD₃OD-d₄, 400 MHz) δ 7.96 (s, 1H), 6.68 (s, 1H), 6.69 (d, J=16.8 Hz,1H), 6.28-6.1 (br s, 1H), 4.81-4.5 (m, 4H), 1.45-1.39 (m, 12H); ³¹P NMR(CD₃OD-d₄) δ −5.84 (s). ESI-LCMS: m/z=450.0 [M+H]⁺.

Example 17 Compounds 32 and 33

To a solution of 42-7 (0.47 g, 0.65 mol) in DCM (3 mL) was added AgNO₃(0.22 g, 1.29 mmol), collidine (0.15 g, 1.29 mmol) and MMTrCl (0.3 g,0.974 mmol) at 0° C. The mixture was stirred at R.T. overnight. Themixture was filtered, and the filter was washed with sat. aq. NaHCO₃solution and brine. The organic layer was separated, dried overanhydrous Na₂SO₄ and concentrated at low pressure. The residue waspurified by silica gel column to give 32-1 (0.55, 85%) as a white solid.

To a solution of 32-1 (0.5 g, 0.5 mmol) in dry DMF (10 mL) was addedNaOBz (0.72 g, 5 mmol) and 15-crown-5 (0.9 mL). The mixture was stirredat 95° C. for 72 h. The mixture was diluted with EA, and washed withwater and brine. The organic phase was dried over MgSO₄ and concentratedat low pressure. The residue was purified by silica gel column (10% EAin PE) to give 32-2 (0.3 g, 60%) as a white solid.

Compound 32-2 (0.3 g, 0.3 mmol) in NH₃/MeOH (30 mL) was stirred at R.T.for 18 h. The mixture was concentrated at low pressure, and the residuewas purified by silica gel column (20% EA in PE) to give 32-3 (145 mg,56%) as a white solid. ESI-LCMS: m/z 890.5 [M+H]⁺.

To a stirred solution of 32-3 (161 mg, 0.16 mmol) in anhydrous CH₃CN(2.0 mL) was added N-methylimidazole (118 μL, 2.87 mmol) at 0 to 5° C.(ice/water bath) followed by solution of 32-4 (186 mg, 0.54 mmol,dissolved in 2 mL of CH₃CN). The solution was stirred at 0 to 5° C. for4 h. The mixture was diluted with EA, and water was added (15 mL). Thesolution was washed H₂O, 50% aqueous citric acid solution and brine. Theorganic layer was separated, dried over anhydrous MgSO₄ and filtered.The filtrate was concentrated in vacuum to give a residue, which waspurified on silica gel with 0 to 40% EA/hexanes to give as 32-5 (82.6mg) as the faster eluting isomer and 32-6 (106 mg) as the slower elutingisomer.

Compound 32-5 (82.6 mg, 0.07 mmol) was dissolved in anhydrous CH₃CN (0.5mL), and 4N HCl in dioxane (35 μL) was added at 0 to 5° C. The mixturewas stirred at R.T. for 1 h, and anhydrous EtOH (100 μL) was added. Thesolvents were evaporated at R.T. and co-evaporated with toluene 3 times.The residue was dissolved in 50% CH₃CN/H₂O, and purified on areverse-phase HPLC (C18) using acetonitrile and water, followed bylyophilization to give compound 32 (19.4 mg). ¹H NMR (CD₃OD-d₄, 400 MHz)7.9 (s, 1H), 7.32-7.28 (t, J=8.0 Hz, 2H), 7.2-7.12 (m, 3H), 6.43 (d,J=17.6 Hz, 1H), 4.70-4.63 (m, 2H), 4.55-4.4 (m, 3H), 3.94-3.9 (m, 1H),1.79-1.67 (m, 4H), 1.53-1.49 (m, 1H), 1.45-1.22 (m, 15H); ³¹P NMR(CD₃OD-d₄) δ 4.06 (s); ESI-LCMS: m/z=655.2 [M+H]⁺, 653.15 [M−H]⁺.

Compound 32-6 (100 mg, 0.083 mmol) was dissolved in anhydrous CH₃CN (0.5mL), and 4N HCl in dioxane (50 μL) was added at 0 to 5° C. Following theprocedure for obtaining compound 32, compound 33 (31.8 mg) was obtained.¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.93 (s, 1H), 7.33-7.29 (m, 2H), 7.24-7.14(m, 3H), 6.41 (d, J=17.6 Hz, 1H), 4.70-4.60 (m, 2H), 4.54-4.49 (m, 2H),4.44-4.39 (m, 1H), 3.92-3.89 (m, 1H), 1.77-1.66 (m, 4H), 1.54-1.24 (m,16H); ³¹P NMR (CD₃OD-d₄) 63.91 (s); ESI-LCMS: m/z=655.2 [M+H]⁺, 653.1[M−H]⁻.

Example 18 Compound 53

Compound 53-1 (70 mg, 58%) was prepared from 32-3 (90 mg; 0.1 mmol) andtriethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.2 mmol)with DIPEA (87 μL), BopCl (44 mg), and 3-nitro-1,2,4-triazole (29 mg) inTHF (2 mL) according to a method described for compound 51-2.Purification was done with hexanes/EtOAc solvent system, 20-80%gradient.

Compound 53 (25 mg, 64%) was prepared from 53-1 (70 mg) in acetonitrile(0.6 mL) and 4 N HCl/dioxane (50 μL) according to a method described forcompound 51. MS: m/z=658 [M+1]⁺.

Example 19 Compounds 40 and 41

To a mixture of pre-silylated 6-Cl-guanine (using HMDS and (NH₄)₂SO₄)(25.2 g, 150 mmol) in DCE (300 mL) was added 40-1 (50 g, 100 mmol) andTMSOTf (33.3 g, 150 mmol) at 0° C. The mixture was stirred at 70° C. for16 h, and then concentrated at low pressure. The residue wasre-dissolved in EA, and washed with sat. aq. NaHCO₃ and brine. Theorganic layer was dried over anhydrous Na₂SO₄, and concentrated at lowpressure. The residue was purified on silica gel column (PE/EA=2/1) togive pure 40-2 (45 g, 73%) as a white solid.

To a solution of 40-2 (45 g, 73.4 mmol) in EtOH (73 mL) was added withEtONa (1N in EtOH, 360 mL). The mixture was stirred at R.T. for 16 h.The mixture was then concentrated to give a residue, which was purifiedby silica gel column (DCM/MeOH=10/1) to give pure 40-3 (19 g, 83%) as awhite solid.

To a solution of 40-3 (19 g, 61.1 mmol) in pyridine (120 mL) was addedwith TIPDSCl₂ (19.2 g, 61 mmol) dropwise at 0° C. The mixture wasstirred at R.T. for 16 h, and then concentrated at low pressure. Theresidue was re-dissolved in EA, and washed with sat. aq. NaHCO₃. Theorganic layer was dried over anhydrous Na₂SO₄, and concentrated at lowpressure. The residue was purified by silica gel column (DCM/MeOH=20/1)to give pure 40-4 (22 g, 65%) as a white solid.

To a solution of 40-4 (22 g, 39.8 mmol) in DMF/pyridine (5/1, 100 mL)was added TMSCl (12.9 g, 119 mmol) dropwise at 0° C. The mixture wasstirred at R.T. for 1 h and then treated with isobutyryl chloride (5.4g, 50 mmol). The mixture was stirred at R.T. for 3 h and then quenchedby NH₄OH. The mixture was concentrated at low pressure. The residue wasdissolved in EA (200 mL). The solution was washed with sat. aq. NaHCO₃,and then the organic layer was dried and concentrated at low pressure.The residue was purified by silica gel column (DCM/MeOH=50/1) to givepure 40-5 (15 g, 60%) as a white solid.

To a solution of 40-5 (15 g, 24.1 mmol) in DCM (100 mL) was added PDC(13.5 g, 26 mmol) and Ac₂O (9.8 g, 96 mmol) at 0° C. The mixture wasstirred at R.T. for 16 h. The reaction was quenched by sat. aq. NaHCO₃,and then extracted with EA. The organic layer was dried over anhydrousNa2SO4, and concentrated at low pressure. The residue was dissolved inanhydrous THF (100 mL). To a solution of TMSCCH (12 g, 112 mmol) in THF(200 mL) was added n-BuLi (2.5 N, 44 mL) at −78° C. The mixture wasstirred at −78° C. for 15 mins and 0° C. for 15 mins. The mixture wastreated with a solution of crude ketone in THF at −78° C. and stirred at−30° C. for 2 h. The reaction was quenched by sat. aq. NH₄Cl, and thenextracted by EA. The combined organic layer was dried over anhydrousNa₂SO₄, and concentrated at low pressure. The residue was purified bysilica gel column (PE/EA=10/1) to give pure 40-6 (3.1 g, 18%) as a whitesolid.

To a solution of 40-6 (7 g, 7.5 mmol) and pyridine (1.4 g, 17 mmol) inDCM (35 mL) was added with DAST (5.6 g, 35 mmol) at −78° C. The mixturewas stirred at −78° C. for 3 h. The reaction was quenched by sat. aq.NaHCO₃, and then extracted with EA. The combined organic layer was driedover anhydrous, and concentrated at low pressure. The residue waspurified by silica gel column (PE/EA=10/1) to give pure 40-7 (3.1 g,18%) as a white solid.

Compound 40-7 (4.1 g, 5.7 mmol) in sat. NH₃/MeOH (100 mL) was stirred atR.T. for 16 h, and concentrated at low pressure. The residue wasre-dissolved in anhydrous DCM (300 mL), and was treated with AgNO₃ (27.0g, 160 mmol), collidine (22 mL) and MMTrCl (23.0 g, 75.9 mmol) in smallportions under N₂. The mixture was stirred at R.T. for 16 h. The mixturewas filtered, and the filtrate was washed with sat. NaHCO₃ solution andbrine. The organic layer was separated, dried over anhydrous Na₂SO₄, andconcentrated at low pressure. The residue was purified by silica gelcolumn (PE/EA=10/1) to give the pure intermediate. The intermediate wasdissolved in a solution of TBAF/THF (1N, 20 mL). The mixture was stirredat R.T. for 2 h and then concentrated at low pressure. The residue waspurified by silica gel column (DCM/MeOH=50/1) to give pure 40-8 (3.0 g,86%) as a white solid.

To a solution of 40-8 (3.0 g, 4.9 mmol) in THF (50 mL) was addedimidazole (840 mg, 12 mmol), PPh₃ (3.2 g, 12 mmol), and I₂ (2.4 g, 9.2mmol) at 0° C. The mixture was stirred at R.T. for 16 h. The reactionwas quenched by sat. aq. Na₂S₂O₃, and then extracted with EA. Thecombined organic layer was dried over anhydrous Na₂SO₄, and concentratedat low pressure. The residue was purified by silica gel column(PE/EA=2/1) to give crude 40-9 (4.2 g, >100%, containing TPPO) as awhite solid.

To a solution of crude 40-9 in anhydrous THF (30 mL) was added DBU (2.7g, 18 mmol), and heated to 80° C. The mixture was stirred for 1 h andchecked by LCMS. The mixture was quenched by water, and extracted withEA. The organic layer was dried over anhydrous Na₂SO₄ and filtered, andthe filtrate was concentrated at low pressure. The residue was purifiedby silica gel column (PE/EA=2/1) to give 40-10 (2.0 g, 69%) as a whitesolid.

To an ice-cooled solution of 40-10 (2.0 g, 3.38 mmol) in anhydrous MeCN(15 mL) was added NIS (777 mg, 3.5 mmol) and NEt₃.3HF (536 g, 3.3 mmol)at 0° C. The mixture was stirred at R.T. for 16 h and checked by LCMS.After completion, the mixture was quenched by sat. Na₂SO₃ and sat.NaHCO₃ solution, and extracted with EA. The organic layer was separated,dried over anhydrous Na₂SO₄ and concentrated at low pressure. Theresidue was purified by silica gel column chromatography (PE/EA=10/1 to3/1) to give 40-11 (2.1 g, 84.0%) as a white solid.

To a solution of crude 40-11 (2.1 g, 2.85 mmol) in anhydrous DCM (100mL) was added DMAP (490 mg, 4 mmol), and BzCl (580 mg, 4 mmol) at 0° C.The mixture was stirred overnight and checked by LCMS. The reaction waswashed with sat. NaHCO₃ solution. The organic layer was dried overanhydrous Na₂SO₄, and concentrated at low pressure. The residue waspurified by silica gel column chromatography (PE/EA=8/1 to 3/1) to give40-12 (2.0 g, 83.4%) as a white solid.

To a solution of 40-12 (2.0 g, 2.4 mmol) in anhydrous DMF (60 mL) wasadded NaOBz (3.3 g, 23.0 mmol) and 15-crown-5 (5.11 g, 23 mmol). Themixture was stirred at 110° C. for 36 h. The reaction was quenched bywater, and the mixture was extracted with EA. The organic layer wasdried over anhydrous Na₂SO₄, and concentrated at low pressure. Theresidue was purified by silica gel column (PE/EA=5/1 to 3/1) to give40-13 (830 mg, 42.0%) as a white solid. ESI-MS: m/z 836.11 [M+H]⁺.

A solution of 40-13 (831 mg, 1.0 mmol) in anhydrous n-butylamine (4 mL)was stirred at R. T. for 3 h under N₂ atmosphere. The reaction wasmonitored by TLC. The solvent was evaporated in vacuo, and the residuewas purified by silica gel column (MeOH in DCM from 0% to 10%) to givethe crude product, which as re-purified using silica gel column to give40-14 as a light pink solid (563 mg).

To a solution of 40-14 (560 mg, 0.89 mmol) in anhydrous pyridine (5 mL)was added imidazole (78.6 mg, 1.16 mmol) and TBSCl (202 mg, 1.34 mmol)at 0 to 5° C. The mixture was stirred at R. T. for 15 h. The reactionwas quenched by adding absolute EtOH (0.3 mL). The solution wasconcentrated to dryness under reduced pressure, and co-evaporated withtoluene 3 times. The residue was dissolved in EA (150 mL), and washedwith water, sat. NaHCO₃, and brine. The combined organic layer was driedover Na₂SO₄, filtered and evaporated at low pressure. The residue waspurified by silica gel column (0-20% EA in hexanes) to give 40-15 (303mg) as a white solid.

To a solution of 40-15 (303 mg, 0.41 mmol), AgNO₃ (208 mg, 1.23 mmol)and collidine (0.55 mL, 4.51 mmol) in anhydrous DCM (4 mL) was addedMMTrCl (378 mg, 1.3 mmol) under N₂. The mixture was stirred at R. T.overnight under N₂, and monitored by TLC. The mixture was filteredthrough pre-packed celite filter, and the filtrate was washed with waterand, 50% aqueous citric acid, and brine. The organic layer wasseparated, dried over anhydrous Na₂SO₄, filtered and concentrated at lowpressure. The residue was purified by silica gel column (EA in hexanesfrom 0% to 30%) to give 40-16 (374 mg, 90%).

To a solution of 40-16 (374 mg, 0.37 mmol) in anhydrous THF (4 mL) wasadded 1.0 M solution of TBAF (0.74 mL, 0.74 mmol) at 0 to 5° C. Themixture was stirred at R.T. for 1 h. The mixture was quenched withsilica gel, and filtered. The solvents were evaporated to give the crudeproduct, which was purified by silica gel column (EA in hexanes from 0%to 50%) to give 40-17 (265 mg).

To a stirred solution of 40-17 (187.5 mg, 0.16 mmol) in anhydrous CH₃CN(2.5 mL) was added N-methylimidazole (136 μL, 1.66 mmol) at 0-5° C.(ice/water bath) followed by solution of phenyl(cyclohexanoxy-L-alaninyl) phosphorochloridate (214 mg, 0.62 mmol,dissolved in 0.5 mL of CH₃CN). The solution was stirred at R.T. for 3 h,and then diluted with EA followed by the addition of water (15 mL). Thesolution was washed with H₂O, 50% aqueous citric acid solution andbrine. The organic layer was separated, dried over anhydrous MgSO₄ andfiltered. The filtrate was concentrated in vacuum to give a residue,which was purified on silica gel with 0 to 40% EA/hexanes to give(single isomers) of 40-18 (108 mg) Elution of the latter fraction gave(single isomers) of 40-19 (120 mg) as glassy solid.

Compound 40-18 (108 mg, 0.089 mmol) was dissolved in anhydrous CH₃CN(0.5 mL), and 4N HCl in dioxane (67 μL) was added at 0 to 5° C.(ice/water bath). The mixture was stirred at R.T. for 40 mins, andanhydrous EtOH (200 μL) was added. The solvents were evaporated at R.T.and co-evaporated with toluene 3 times. The residue was dissolved in 50%CH₃CN/H₂O, was purified on a reverse-phase HPLC (C18) using acetonitrileand water, followed by lyophilization to give compound 40 (26.6 mg) as awhite foam. ¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.89 (s, 1H), 7.33-7.29 (m,2H), 7.20-7.13 (m, 3H), 7.17 (m, 1H), 6.62 (d, J=15.6 Hz, 1H), 5.39 (t,J=25.2 Hz, 1H), 4.75-4.42 (m, 6H), 3.92 (t, J=8.8 Hz, 1H), 3.24 (d,J=5.6 Hz, 1H), 1.76-1.51 (m, 5H), 1.45-1.25 (m, 12H); ³¹P NMR (CD₃OD-d₄)64.04 (s); ESI-LCMS: m/z=665.2 [M+H]⁺.

Compound 41 (44.4 mg, single isomer) was obtained according to theprocedure described for compound 40 using 40-19. ¹H NMR (CD₃OD-d₄, 400MHz) δ 7.93 (s, 1H),), 7.32 (t, J=8.0 Hz, 1H), 7.24 (d, J=7.6 Hz, 2H),7.16 (t, J=7.6 Hz, 1H), 6.61 (d, J=16.0 Hz, 1H), 4.68-4.60 (m, 2H),4.54-4.39 (m, 3H), 3.93-3.89 (m, 1H), 3.24 (d, J=5.6 Hz, 1H), 1.75-1.5(m, 5H), 1.48-1.23 (m, 12H); ¹⁹F NMR (CD₃OD-d₄) δ −122.95 (s),−155.84-155.99 (m); ³¹P NMR (CD₃OD-d₄) δ 3.94 (s); ESI-LCMS: m/z=665.15[M+H]⁺.

Example 20 Compound 49

To a solution of triethylammoniumbis(isopropyloxycarbonyloxymethyl)phosphate (0.33 mmol, prepared from110 mg of bis(POC)phosphate and 46 μL of Et₃N) in THF was added 49-1 (91mg, 0.11 mmol). The mixture evaporated and rendered anhydrous byco-evaporating with pyridine follow by toluene. The residue wasdissolved in anhydrous THF (1.5 mL) and cooled in an ice-bath.Diisopropylethyl amine (0.19 mL, 10 eq.) was added, followed by BOP-Cl(0.14 g, 5 eq.), and 3-nitro-1,2,4-triazole (63 mg, 5 eq.). The mixturewas stirred 0° C. for 90 mins, diluted with EtOAc (30 mL), washed withsat. aq. NaHCO₃, brine, and dried (Na₂SO₄). The residue was purified onsilica (10 g column) with CH₂Cl₂/i-PrOH solvent system (2-10% gradient)to obtain 49-2 (13 mg, 10%) and 49-3 (95 mg, 58%).

A solution of 49-2 and 49-3 (13 mg and 95 mg, respectively) in 80% aq.HCOOH (3 mL) was stirred at R.T. for 3 h, then evaporated andco-evaporated with toluene. The residue was purified on silica (10 gcolumn) with CH₂Cl₂/MeOH (4-10% gradient) to obtain compound 49 in (42mg, 94%) yield. MS: m/z=628 [M+1]⁺.

Example 21 Compound 52

Compound 52-2 (158 mg, 50%) was from 52-1 (0.21 g; 0.35 mmol) andtriethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.54 mmol)with DIPEA (0.18 mL), BopCl (178 mg), and 3-nitro-1,2,4-triazole (80 mg)in THF (4 mL).

A solution of 52-2 (158 mg) in acetonitrile (1 mL) and HCl (4 N/dioxane;85 μL) was stirred at R.T. for 30 mins. The reaction was quenched withMeOH and concentrated. The residue was purified on silica gel (10 gcolumn) with CH₂Cl₂/i-PrOH (3-10% gradient) to give compound 52 (85 mg,76%). MS: m/z=656 [M+1]⁺.

Example 22 Compound 11

A mixture of 11-1 (170 mg, 0.19 mmol) and methanolic ammonia (7 N; 3 mL)was stirred at R.T. for 8 h, concentrated and purified on silica gel (10g column) with CH₂Cl₂/MeOH (4-11% gradient) to give 11-2 (100 mg, 90%).

Compound 11-2 was rendered anhydrous by co-evaporating with pyridine,followed by toluene. To a solution of 11-2 (24 mg, 0.04 mmol), andN-methylimidazole (17 μL, 5 eq.) in acetonitrile (1 mL) was added thephosphorochloridate (50 mg, 3.5 eq.) in 2 portions in 6 h intervals. Themixture was stirred at R.T. for 1 d and evaporated. Purification onsilica (10 g column) with CH₂Cl₂/MeOH (4-12% gradient) yielded 11-3 (10mg, 28%).

A solution of 11-3 (9 mg, 0.01 mmol) in 80% formic acid was stirred 3 hat R.T. The mixture was evaporated and purified on silica (10 g column)with CH₂Cl₂/MeOH (5-15% gradient) to give compound 11 (3 mg, 50%). MS:m/z=624 [M−1]⁻.

Example 23 Compound 14

A mixture of 14-1 (1.2 g, 4.3 mmol), PTSA monohydrate (0.82 g, 1 eq.),and trimethyl orthoformate (14 mL, 30 eq.) in dioxane (30 mL) wasstirred overnight at R.T. The reaction was neutralized with 7 N NH₃/MeOHand a white solid removed by filtration. The residue was dissolved inTHF (10 mL) and treated with 80% aq. AcOH (5 mL). The mixture was keptat R.T. for 45 mins and then evaporated. The residue was purified onsilica gel (25 g column) with CH₂Cl₂/MeOH (4-10% gradient) to give 14-2(1.18 g, 87%).

Compound 14-3 (137 mg, 75%) was prepared from 14-2 (93 mg, 0.29 mmol)and triethylammonium bis(isopropyloxycarbonyloxymethyl)phosphate (0.44mmol) with DIPEA (0.2 mL), BopCl (147 mg), and 3-nitro-1,2,4-triazole(66 mg) in THF (3 mL). Purification was done with CH₂Cl₂/i-PrOH solventsystem (3-10% gradient).

A solution of 14-3 (137 mg) in 80% aq. HCOOH was stirred at R.T. for 2h, and then concentrated. The residue was co-evaporated with toluene andthen MeOH containing a small amount of a small amount of Et₃N (2 drops).Purification on silica (25 g column) with CH₂Cl₂/MeOH (4-10% gradient)gave compound 14 (100 mg, 77%). MS: m/z=1175 [2M−1]⁻.

Example 24 Compound 16

Compound 16-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol)were co-evaporated with anhydrous toluene 3 times. To a solution of 10-1in MeCN (200 mL) was added DBU (39.5 g, 258.0 mmol) at 0° C. The mixturewas stirred at 0° C. for 30 mins, and then TMSOTf (95.5 g, 430.0 mmol)was added dropwise at 0° C. The mixture was stirred at 0° C. for 30mins. The mixture was heated to 70° C., and stirred overnight. Thesolution was cooled to R.T. and diluted with EA (100 mL). The solutionwas washed with sat. NaHCO₃ solution and brine. The organic layer wasdried over Na₂SO₄, and concentrated at low pressure. The residue waspurified by column on silica gel (EA in PE from 10% to 40%) to give 16-2(48.0 g, yield: 88.7%) as a yellow foam. ESI-MS: m/z 628 [M+H]⁺.

To a solution of 16-2 (48.0 g, 76.4 mol), AgNO₃ (50.0 g, 294.1 mmol) andcollidine (40 mL) in anhydrous DCM (200 mL) was added MMTrCl (46.0 g,149.2 mmol) in small portions under N₂. The mixture was stirred at R.T.for 3 h under N₂ The reaction was monitored by TLC. The mixture wasfiltered, and the filter was washed with sat. NaHCO₃ solution and brine.The organic layer was dried over anhydrous Na₂SO₄, and concentrated atlow pressure. The residue was purified by silica gel column (EA in PEfrom 5% to 50%) to the give crude 16-3 (68 g, 98%). ESI-MS: m/z 900.1[M+H]⁺.

Sodium (8.7 g, 378.0 mmol) was dissolved in dry EtOH (100 mL) at 0° C.,and slowly warmed to R.T. Compound 16-3 (68.0 g, 75.6 mmol) was treatedwith freshly prepared NaOEt solution, and stirred overnight at R.T. Thereaction was monitored by TLC, and the mixture was concentrated at lowpressure. The mixture was diluted with H₂O (100 mL), and extracted withEA (3×100 mL). The organic layer was dried over anhydrous Na₂SO₄, andevaporated at low pressure. The residue was purified by silica gelcolumn chromatography (MeOH in DCM from 1% to 5%) to give 16-4 (34.0 g,75.2%) as a yellow solid. ESI-MS: m/z 598 [M+H]⁺.

Compound 16-4 (32.0 g, 53.5 mmol) was co-evaporated with anhydrouspyridine 3 times. To an ice-cooled solution of 16-4 in anhydrouspyridine (100 mL) was added TsCl (11.2 g, 58.9 mmol) in pyridine (50 mL)dropwise at 0° C. The mixture was stirred for 18 h. at 0° C. Thereaction was checked by LCMS (about 70% was the desired product). Thereaction was quenched with H₂O, and the solution was concentrated at lowpressure. The residue was dissolved in EA (100 mL), and washed with sat.NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄, andevaporated at low pressure. The residue was purified by silica gelcolumn chromatography (MeOH in DCM from 1% to 5%) to give crude 16-5(25.0 g, 62.2%) as a yellow solid. ESI-MS: m/z 752 [M+H]⁺.

To a solution of 16-5 (23.0 g, 30.6 mmol) in acetone (150 mL) was addedNaI (45.9 g, 306.0 mmol) and TBAI (2.0 g), and refluxed overnight. Thereaction was monitored by LCMS. After the reaction was complete, themixture was concentrated at low pressure. The residue was dissolved inEA (100 mL), washed with brine, and dried over anhydrous Na₂SO₄. Theorganic solution was evaporated at low pressure. The residue waspurified by silica gel column chromatography (DCM: MeOH=100:1 to 20:1)to give the crude product. To a solution of the crude product in dry THF(200 mL) was added DBU (14.0 g, 91.8 mmol), and heated to 60° C. Themixture was stirred overnight, and checked by LCMS. The reaction wasquenched with sat. NaHCO₃, and the solution was extracted with EA (100mL). The organic layer was dried over anhydrous Na₂SO₄, and evaporatedat low pressure. The residue was purified by silica gel columnchromatography (MeOH in DCM from 1% to 5%) to give 16-6 (12.0 g, 67.4%)as a yellow solid. ESI-MS: m/z 580 [M+H]⁺.

To an ice-cooled solution of 16-6 (8.0 g, 13.8 mmol) in dry MeCN (100mL) was added NIS (3.9 g, 17.2 mmol) and TEA.3HF (3.3 g, 20.7 mmol) at0° C. The mixture was stirred at R.T. for 18 h and checked by LCMS.After the reaction was complete, the reaction was quenched with satNa₂SO₃ and sat. NaHCO₃ solution. The solution was extracted with EA. Theorganic layer was dried over anhydrous Na₂SO₄, and evaporated at lowpressure. The residue was purified by silica gel column chromatography(EA in PE from 10% to 50%) to give 16-7 (7.2 g, 72.0%) as a solid.ESI-MS: m/z 726 [M+H]⁺.

To a solution of crude 16-7 (7.2 g, 9.9 mmol) in dry DCM (100 mL) wasadded DMAP (3.6 g, 29.8 mmol), and BzCl (2.8 g, 19.8 mmol) at 0° C. Themixture was stirred overnight, and checked by LCMS. The mixture waswashed with sat. NaHCO₃ solution. The organic layer was dried overanhydrous Na₂SO₄, and evaporated at low pressure. The residue waspurified by silica gel column chromatography (EA in PE from 10% to 30%)to give 16-8 (8.0 g, 86.4%) as a solid. ESI-MS: m/z 934 [M+H]⁺.

To a solution of 16-8 (7.5 g, 8.0 mmol) in dry DMF (100 mL) was addedNaOBz (11.5 g, 80.0 mmol) and 15-crown-5 (15.6 mL). The mixture wasstirred for 36 h. at 90° C. The mixture was diluted with H₂O (100 mL),and extracted with EA (3×150 mL). The organic layer was dried overanhydrous Na₂SO₄, and evaporated at low pressure. The residue waspurified by silica gel column chromatography (EA in PE from 10% to 30%)to give crude 16-9 (6.0 g, 80.0%) as a solid. ESI-MS: m/z 928 [M+H]⁺.

Compound 16-9 (4.0 g, 4.3 mmol) was co-evaporated with anhydrous toluene3 times, and treated with NH₃/MeOH (50 mL, 4N) at R.T. The mixture wasstirred for 18 h at R.T. The reaction was monitored by LCMS, and themixture was concentrated at low pressure. The residue was purified bysilica gel column chromatography (EA in PE from 30% to 50%) to give16-10 (1.9 g, 71.7%) as a solid. ESI-MS: m/z 616 [M+H]⁺.

Compound 16-10 (300.0 mg, 0.49 mmol) was co-evaporated with anhydroustoluene 3 times, and was dissolved in MeCN (2 mL). The mixture wastreated with NMI (120.5 mg, 1.47 mmol) and the phosphorochloridatereagent (338.1 mg, 0.98 mmol) in MeCN (1 mL) at 0° C. The mixture wasstirred for 18 h at R. T. The reaction was monitored by LCMS. Themixture was diluted with 10% NaHCO₃ solution, and extracted with EA. Theresidue was purified by silica gel column chromatography (EA in PE from30% to 50%) to give 16-11 (240 mg, 53.3%) as a solid. ESI-MS: m/z 925[M+H]⁺.

Compound 16-11 (240.0 mg, 0.26 mmol) was treated with 80% AcOH (10 mL),and the mixture was stirred for 18 h at R.T. The reaction was monitoredby LCMS. The mixture was concentrated at low pressure. The residue waspurified by silica gel column chromatography (MeOH in DCM from 1% to 3%)to give compound 16 (87.6 mg, 51.7%) as a solid. ESI-MS: m/z 653 [M+H]⁺.

Example 25 Compound 30

To a stirred solution of compound 25 (60 mg, 0.22 mmol) in anhydrous THF(2.0 mL) was added N-methylimidazole (0.142 mL, 1.73 mmol) at 0° C. (dryice/acetone bath) followed by solution of phenyl(cyclohexanoxy-L-alaninyl) phosphorochloridate (235 mg, 0.68 mmol,dissolved in THF (2 mL). The resulting solution was stirred at 0° C. for1 h, and the temperature was raised up-to 10° C. over the next 1 h. Thereaction left at 10° C. for 3 h. The mixture was cooled to 0 to 5° C.,diluted with EA, and water (5 mL) was added. The solution was washedwith H₂O and brine. The organic layer was separated, dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuumto give a residue, which dissolved in 25% CH₃CN/H₂O. The compound waspurified on a reverse-phase HPLC (C18) using acetonitrile and water,followed by lyophilization gave a white foam. The produce wasre-dissolved in EtOAc, washed with 50% aqueous citric acid solution,dried over anhydrous MgSO₄ and filtered. The filtrate was concentratedin vacuum, and lyophilized to give two isomers (Rp/Sp) of compound 30(6.3 mg). MS: m/z 586.05 [M−H]⁻.

Example 26 Compound 17

Compound 17-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol)were co-evaporated with anhydrous toluene 3 times. To a solution of 17-1(50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol) in MeCN (200 mL)was added DBU (39.5 g, 258.0 mmol) at 0° C. The mixture was stirred at0° C. for 30 mins, and TMSOTf (95.5 g, 430.0 mmol) was added dropwise at0° C. The mixture was stirred at 0° C. for 30 mins until a clearsolution was observed. The mixture was heated to 70° C., and stirredovernight. The solution was cooled to R.T., and diluted with EA (100mL). The solution was washed with sat. NaHCO₃ solution and brine. Theorganic layer was dried over Na₂SO₄, and concentrated at low pressure.The residue was purified by column on silica gel (EA in PE from 10% to40%) to give 17-2 (48.0 g, 88.7%) as a yellow foam. ESI-MS: m/z 628[M+H]⁺.

To a solution of 17-2 (48.0 g, 76.4 mol), AgNO₃ (50.0 g, 294.1 mmol) andcollidine (40 mL) in anhydrous DCM (200 mL) was added MMTrCl (46.0 g,149.2 mmol) in small portions under N₂. The mixture was stirred at R.T.for 3 h under N₂. Completion of the reaction was determined by TLC.After filtration, the filtrate was washed with sat. NaHCO₃ solution andbrine. The organic layer was dried over anhydrous Na₂SO₄, andconcentrated at low pressure. The residue was purified by silica gelcolumn (EA in PE from 5% to 50%) to the give crude 17-3 (68 g, 98%).ESI-MS: m/z 900.1 [M+H]⁺.

Sodium (8.7 g, 378.0 mmol) was dissolved in dry EtOH (100 mL) at 0° C.,and slowly warmed to R.T. Compound 17-3 (68.0 g, 75.6 mmol) was treatedwith freshly prepared NaOEt solution, and stirred overnight at R.T.Completion of the reaction was determined by TLC and LCMS. The mixturewas concentrated at a low pressure, diluted with H₂O (100 mL), andextracted with EA (3×100 mL). The organic layer was dried over anhydrousNa₂SO₄, and evaporated at low pressure. The residue was purified bysilica gel column chromatography (MeOH in DCM from 1% to 5%) to give17-4 (34.0 g, 75.2%) as a yellow solid. ESI-MS: m/z 598 [M+H]⁺.

Compound 17-4 (32.0 g, 53.5 mmol) was co-evaporated with anhydrouspyridine 3 times. To an ice-cooled solution of 17-4 (32.0 g, 53.5 mmol)in anhydrous pyridine (100 mL) was added a solution of TsCl (11.2 g,58.9 mmol) in pyridine (50 mL) dropwise at 0° C. The mixture was stirredfor 18 h. at 0° C. The reaction was monitored by LCMS, and quenched withH₂O. The solution was concentrated at low pressure, and the residue wasdissolved in EA (100 mL), and washed with sat. NaHCO₃ solution. Theorganic layer was dried over anhydrous Na₂SO₄, and evaporated at a lowpressure. The residue was purified by silica gel column chromatography(MeOH in DCM from 1% to 5%) to give crude 17-5 (25.0 g, 62.2%) as ayellow solid. ESI-MS: m/z 752 [M+H]⁺.

To a solution of 17-5 (23.0 g, 30.6 mmol) in acetone (150 mL) was addedNaI (45.9 g, 306.0 mmol) and TBAI (2.0 g), and the mixture was refluxedovernight. Completion of the reaction was determined by LCMS. Themixture was concentrated at low pressure, and the residue was dissolvedin EA (100 mL). The solution was washed with brine, and dried overanhydrous Na₂SO₄. The organic solution was evaporated at low pressure,and the residue was purified by silica gel column chromatography (DCM:MeOH=100:1 to 20:1) to give a crude product. To a solution of the crudeproduct in dry THF (200 mL) was added DBU (14.0 g, 91.8 mmol), and themixture was heated to 60° C. and stirred overnight. The reaction wasmonitored by LCMS. The reaction was quenched with sat. NaHCO₃ solution,and the solution was extracted with EA (100 mL). The organic layer wasdried over anhydrous Na₂SO₄, and evaporated at low pressure. The residuewas purified by silica gel column chromatography (MeOH in DCM from 1% to5%) to give 17-6 (12.0 g, 67.4%) as a yellow solid. ESI-MS: m/z 580[M+H]⁺.

To an ice-cooled solution of 17-6 (8.0 g, 13.8 mmol) in anhydrous MeCN(100 mL) was added NIS (3.9 g, 17.2 mmol) and TEA.3HF (3.3 g, 20.7 mmol)at 0° C. The mixture was stirred at R.T. for 18 h, and the reaction waschecked by LCMS. After the reaction was completed, the reaction wasquenched with sat. Na₂SO₃ solution and sat. NaHCO₃ solution. Thesolution was extracted with EA (3×100 mL). The organic layer was driedover anhydrous Na₂SO₄, and evaporated at low pressure. The residue waspurified by silica gel column chromatography (EA in PE from 10% to 50%)to give 17-7 (7.2 g, 72.0%) as a solid. ESI-MS: m/z 726 [M+H]⁺.

To a solution of 17-7 (7.2 g, 9.9 mmol) in dry DCM (100 mL) was addedDMAP (3.6 g, 29.8 mmol), and BzCl (2.8 g, 19.8 mmol) at 0° C. Themixture was stirred overnight, and checked by LCMS. The mixture waswashed with sat. NaHCO₃ solution. The organic layer was dried overanhydrous Na₂SO₄, and evaporated at low pressure. The residue waspurified by silica gel column chromatography (EA in PE from 10% to 30%)to give 17-8 (8.0 g, 86.4%) as a solid. ESI-MS: m/z 934 [M+H]⁺.

To a solution of 17-8 (7.5 g, 8.0 mmol) in dry DMF (100 mL) was addedNaOBz (11.5 g, 80.0 mmol) and 15-crown-5 (15.6 mL). The mixture wasstirred for 36 h. at 90° C. The mixture was diluted with H₂O (100 mL),and extracted with EA (3×150 mL). The organic layer was dried overanhydrous Na₂SO₄, and evaporated at low pressure. The residue waspurified by silica gel column chromatography (EA in PE from 10% to 30%)to give crude 17-9 (6.0 g, 80.0%) as a solid. ESI-MS: m/z 928 [M+H]⁺.

Compound 17-9 (4.0 g, 4.3 mmol) was co-evaporated with anhydrous toluene3 times, and treated with NH₃/MeOH (50 mL, 4N) at R.T. The mixture wasstirred for 18 h. at R.T. Completion of the reaction was determined byLCMS. The mixture was concentrated at low pressure, and the residue waspurified by silica gel column chromatography (EA in PE from 30% to 50%)to give product 17-10 (1.9 g, 71.7%) as a solid. ESI-MS: m/z 616 [M+H]⁺.

Compound 17-10 (300.0 mg, 0.49 mmol) was co-evaporated with anhydroustoluene 3 times, and was dissolved in MeCN (2 mL). The mixture wastreated with NMI (120.5 mg, 1.47 mmol) and the phosphorochloridatereagent (326.3 mg, 0.98 mmol) in MeCN (1 mL) at 0° C. The mixture wasstirred for 18 h at R.T. and monitored by LCMS. The mixture was dilutedwith 10% NaHCO₃ solution, and extracted with EA (3×30 mL). The residuewas purified by silica gel column chromatography (EA in PE from 30% to50%) to give 17-11 (210 mg, 47.5%) as a solid. ESI-MS: m/z 913.0 [M+H]⁺.

Compound 17-11 (210 mg, 0.26 mmol) was treated with 80% of AcOH (15 mL),and the mixture was stirred for 18 h at R.T. Completion of the reactionwas determined by LCMS. The mixture was concentrated at low pressure,and the residue was purified by silica gel column chromatography (MeOHin DCM from 1% to 3%) to give compound 17 (71.8 mg, 48.7%) as a solid.ESI-MS: m/z 641.3 [M+H]⁺.

Example 27 Compounds 9, 12, 15, 26, 28, 38, 44, 46, 50, 63, 64, 69 and76

Compounds 9, 12, 15, 26, 28, 38, 44, 46, 50, 63, 64, 69 and 76 wereprepared in a manner similar to method for preparing compound 6. Afterthe addition of POCl₃, the mixture was kept at R.T. for 20-40 mins. Thereaction was controlled by LCMS and monitored by the appearance ofcorresponding nucleoside 5′-monophosphate. After completion of thereaction, tetrabutylammonium salt of pyrophosphate (150 mg) was added,followed by DMF (0.5 mL) to get a homogeneous solution. After 1.5 h atambient temperature, the reaction was diluted with water (10 mL). Thetriphosphate (eluted at 75-80% B) were obtained as described forcompound 6.

MS ³¹P NMR Structure [M − 1]⁻ P(α) P(β) P(γ)

556.2 −10.92   −11.03(d) −23.18(t) −11.86   −11.98(d)

516.1  −7.49    −7.61(d) −22.42(t) −12.17   −12.30(d)

554.0 −10.94   −11.06(d) −23.25(t) −11.85   −11.97(d)

525.2 −8.53(bs) −22.61 (bs) −12.17   −12.29(d)

564.4 −11.05 (bs) −23.25 (bs) −11.96   −12.08(d)

566.0 −10.92   −11.04(d) −23.18(t) −11.93  −1(d)

533.3 −10.89   −11.01(d) −23.31(t) −12.49  −1(d)

513.8 −8.66(bs) −22.80(t) −12.17   −12.29(d)

517.7 −13.73   −13.60(d) −25.98(t) −15.18   −15.06(d)

539.5 −7.42 (br.s) −22.57(t) −12.23   −12.34(d)

513.1  −6.36    −6.49(d) −22.49(t) −12.20   −12.33(d)

526.8 −10.96   −11.08(d) −23.33(t) −12.41   −12.53(d)

533.4 −10.78 (br.s) −23.22(t) −12.24   −12.36(d)

The following compounds can also be prepared using a method similar tothe method described in Example 27:

Example 28 Compound 10

Compound 10-1 (5 g, 8.79 mmol) was co-evaporated with anhydrouspyridine. To an ice-cooled solution of 10-1 in anhydrous pyridine (15mL) was added TsCl (3.43 g, 17.58 mmol), and stirred for 1 h at 0° C.The reaction was checked by LCMS and TLC. The reaction was quenched withH₂O, and extracted with EA. The organic phase was dried over anhydrousNa₂SO₄, and evaporated at low pressure. Compound 10-2 (6.35 g, 100%) wasused for next step directly.

To a solution of 10-2 (31.77 g, 43.94 mmol) in acetone (300 mL) wasadded NaI (65.86 g, 439.4 mmol), and heated to reflux overnight. Thereaction was checked by LCMS. The reaction was quenched with sat.Na₂S₂O₃ solution, and extracted with EA. The organic layer was driedover anhydrous Na₂SO₄, and evaporated at low pressure. The residue waspurified by silica gel column chromatography (MeOH in DCM from 1% to 6%)to give 10-3 (11.5 g, 38%) as a white solid.

To a solution of 10-3 (11.5 g, 16.94 mmol) in dry THF (120 mL) was addedDBU (12.87 g, 84.68 mmol), and heated to 60° C. The reaction was stirredovernight and checked by LCMS. The reaction was quenched with sat.NaHCO₃ solution, and extracted with EA. The organic phase was dried overanhydrous Na₂SO₄, and evaporated at low pressure. The residue waspurified by silica gel column chromatography (MeOH in DCM from 1% to 5%)to give 10-4 (5.5 g, 54%) as a white solid.

To an ice-cooled solution of 10-4 (500 mg, 0.90 mmol) in dry DCM (20 ml)was added AgF (618 mg, 4.9 mmol) and a solution of I₂ (500 mg, 1.97mmol) in dry DCM (20 mL). The reaction was stirred for 3 h., and checkedby LCMS. The reaction was quenched with sat Na₂S₂O₃ solution and sat.NaHCO₃ solution, and the mixture was extracted with DCM. The organiclayer was dried by anhydrous Na₂SO₄, and evaporated at low pressure togive crude 10-5 (420 mg, 66%).

To a solution of crude 10-5 (250 mg, 0.36 mmol) in dry DCM (8 mL) wasadded DMAP (0.28 g, 2.33 mmol), TEA (145 mg, 1.44 mmol) and BzCl (230mg, 1.62 mmol) in a solution of DCM (2 mL). The reaction was stirredovernight, and checked by LCMS. The mixture was washed with sat. NaHCO₃solution and brine. The organic layer was evaporated at low pressure.The residue was purified by prep-TLC to give crude 10-6 (150 mg, 46%).

To a solution of crude 10-6 (650 mg, 0.72 mmol) in dry HMPA (20 mL) wasadded NaOBz (1.03 g, 7.2 mmol) and 15-crown-5 (1.59 g, 7.2 mmol). Thereaction was stirred for 2 d at 60° C. The mixture was diluted with H₂O,and extracted with EA. The organic layer was evaporated at low pressure.The residue was purified by prep-TLC to give 10-7 (210 mg, 32.4%).ESI-MS: m/z: 900.4 [M+H]⁺.

A mixture of 10-7 (25 mg) and BuNH₂ (0.8 mL) was stirred overnight atR.T. The mixture was evaporated and purified on silica gel (10 g column)with CH₂Cl₂/MeOH (4-15% gradient) to yield 10-8 (15 mg, 91%).

A mixture of 10-8 (15 mg, 0.02 mmol) in ACN (0.25 mL) and 4 NHCL/dioxane (19 uL) was stirred at R.T. for 45 mins. The mixture wasdiluted with MeOH and evaporated. The crude residue was treated withMeCN, and the solid was filtered to yield compound 10 (7 mg). MS:m/z=314 [M−1]⁻.

Example 29 Compounds 36 and 37

To a solution of 36-1 (150 mg, 0.24 mmol) in DCM (2.0 mL), triethylamine(141 μL, 2.0 mmol) was added at R.T. The mixture was cooled to 0 to 5°C. (ice/water bath), and freshly prepared and distilled isopropylphosphorodichloridate (45 μL, 0.26 mmol, prepared according to aprocedure, Reddy et al. J. Org. Chem. 2011, 76 (10), 3782-3790) wasadded. The mixture was stirred at 0 to 5° C. (ice/water bath) for 15mins, followed by N-methylimidazole (40 μL, 0.49 mmol). The mixture wasstirred for 1 h at 0 to 5° C. TLC showed the absence of startingmaterial 36-1. EA (100 mL) was added, followed by water. The organiclayer was washed with H₂O, sat. aq. NH₄Cl solution and brine. Theorganic layer was separated, dried over anhydrous MgSO₄ and filtered.The filtrate was concentrated in vacuum to give a residue, which waspurified on silica gel with 0 to 10% iPrOH/DCM to give 36-2a (16.9 mg,faster eluting isomer) and 36-2b (72.7 mg, slower eluting isomer).

Compounds 36-2a and 36-2b were deprotected using a procedure describedherein. Compound 36 (7.3 mg, single isomers from 36-2a (16.5 mg, 0.0235mmol)) and compound 37 (29.0 mg. single isomers from 36-2b (72.7 mg, 0.1mmol)) were obtained.

Compound 36: ¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.94 (s, 1H), 6.32 (s, 1H),6.00-5.9 (br s, 1H), 4.9-4.487 (m, 1H), 4.83-4.77 (m, 1H), 4.65-4.50 (m,3H), 1.45-1.39 (s, 9H), 1.2 (s, 3H); ¹⁹F NMR (CD₃OD-d₄) δ −120.3 (s);³¹P NMR (CD₃OD-d₄) δ −5.19 (s); ESI-LCMS: m/z=448.05 [M+H]⁺. Compound37: ¹H NMR (CD₃OD-d₄, 400 MHz) δ 7.98 (s, 1H), 6.34 (s, 1H), 5.78-5.64(br s, 1H), 4.95-4.48 (m, 2H), 4.62-4.52 (m, 3H), 1.48-1.42 (s, 9H), 1.1(s, 3H); ¹⁹F NMR (CD₃OD-d₄) δ −121.3 (s); ³¹P NMR (CD₃OD-d₄) δ −7.38(s); ESI-LCMS: m/z=448.05 [M+H]⁺.

Example 30 Compound 48

To a solution of 48-1 (600 mg, 1.29 mmol) in anhydrous CH₃CN (4 mL) wasadded DMAP (315 mg, 2.59 mmol), TEA (391 mg, 3.87 mmol) and TPSCl (782mg, 2.58 mmol). The mixture was stirred for 3 h. under N₂. A solution ofNH₃ in THF (2 mL) was added, and stirred for 1 h. The reaction wasquenched with sat. NH₄Cl solution, and extracted with EA. The organiclayer was dried over anhydrous Na₂SO₄, and concentrated to dryness atlow pressure. The residue was purified by column chromatography toprovide 48-2 (370 mg, 62%) as a white foam solid.

Compound 48-2 (370 mg, 1.48 mmol) in methanolic ammonium was stirred atR.T. for 4 h. The solution was concentrated to dryness to give compound48 (200 mg, 91%) as a white solid. ESI-MS: m/z 275.9 [M+H]⁺.

Example 31 Compounds 18 and 19

The diastereomers of compound 2 were separated by RP-HPLC. A gradient of10-43% ACN in H₂O over 26 mins on a Synergi Hydro RP 30×250 m 4uparticle column (Phenomenex PN 00G-4375-U0-AX) eluted compound 19 (29.5mins) and compound 18 (30.1 mins). Pure fractions were lyophilized toproduce a white powder. Compound 19: ³¹P-NMR (DMSO-d6) 3.448 ppm; MS:m/z: 544 [M−1]⁻; Compound 18: ³¹P-NMR (DMSO-d6) 3.538 ppm; MS: m/z: 544[M−1]⁻.

Example 32 Compounds 20 and 21

The diastereomers of compound 3 were separated by RP-HPLC. A gradient of25-52% ACN in H₂O over 26 mins on a Synergi Hydro RP 30×250 m 4uparticle column (Phenomenex PN 00G-4375-U0-AX) eluted compound 21 (24.8mins) and compound 20 (25.3 mins). Pure fractions were lyophilized toproduce a white powder. Compound 21: ³¹P-NMR (DMSO-d6) 3.492 ppm; MS:m/z: 584 [M−1]⁻. Compound 20: ³¹P-NMR (DMSO-d6) 3.528 ppm; MS: m/z: 584[M−1]⁻.

Example 33 Compound 13

Compound 2-1 (32 mg, 0.1 mmol) was dissolved in dry THF (3 mL) and 2Msolution of isopropylmagnesium bromide in THF (0.1 mL) was added at 0°C. The reaction was left for 1 h at R.T., andphenyl(isopropyl-L-alaninyl) thiophosphorochloridate was added (0.3mmol). The mixture was left overnight at R.T. LSMS analysis showed about20% of unreacted starting material. The same amount of Grignard reagentand thiophosphorochloridate were added, and the mixture was heated at37° C. for 4 h. The reaction was quenched with NH₄Cl. The product wasextracted with EA, washed with brine, dried over Na₂SO₄, and evaporated.The resulting oil was dissolved in 80% formic acid (4 mL) and in 1 hevaporated. Compound 13 was purified by RP HPLC in gradient of methanolin water from 30% to 95% on Synergy 4u Hydro-RP column (Phenominex)yielding a colorless solid. Compound 13 (7 mg, yield 12.5%). MS: m/z:560.0 [M−1]⁻.

Example 34 Compound 39, Bis-lithium Salt

Compound 39-1 was synthesized using a procedure similar for preparingcompound 2 using alanine benzyl ester hydrochloride. LCMS: m/z 592[M−1]⁻.

To a solution of 39-1 (1.1 g, 1.85 mmol) in dioxane (15 mL) and water (3mL) was added aqueous triethylammonium acetate (2M, 2 mL, 4 mmol)followed by Pd—C (10%, 100 mg). The mixture was hydrogenated (balloon)for 2 h, and monitored by HPLC. The catalyst was filtered off, and thefiltrate was concentrated to dryness. The residue was suspended in 3%solution of lithium perchlorate in acetone (25 mL). The solid wasisolated by filtration, rinsed with acetone and dried under vacuum togive compound 39 (bis-lithium salt) (731 mg, 90%). LCMS: m/z 426 [M−1]⁻.

Example 35 Compound 55

Compound 1 (40 mg, 0.14 mmol) and triethylammoniumbis(pivaloyloxymethyl)phosphate (0.21 mmol, prepared from 80 mg ofbis(pivaloyloxymethyl)phosphate and 30 μL of Et₃N) were renderedanhydrous by coevaporating with pyridine, followed by toluene. Theevaporated residue was dissolved in anhydrous THF (2 mL) and cooled inan ice-bath. Diisopropylethyl amine (73 μL, 3 eq.), BopCl (71 mg, 2eq.), and 3-nitro-1,2,4-triazole (32 mg, 2 eq.) were added. The mixturewas stirred at 0° C. for 90 mins. The mixture was then diluted withEtOAc, washed with sat. aq. NaHCO₃ and brine, and dried (Na₂SO₄).Purification on silica gel column with CH₂Cl₂/i-PrOH solvent system(4-10% gradient) followed by RP-HPLC purification (A: water, B: MeCN)yielded compound 55 (13 mg, 16%). MS: m/z=1167 [2M−1].

Example 36 Compound 45

Compound 45-1 (15.0 g, 25.55 mmol) was treated with 90% HOAc (150 mL) atR.T. The mixture was stirred at 110° C. for 12 h, and then concentratedat a low pressure. The residue was dissolved in DCM, and the solutionwas washed with brine. The organic phase was dried over anhydrousNa₂SO₄, and then concentrated at a low pressure. The residue waspurified by column chromatography (5% MeOH in DCM) to give 45-2 (11.0 g,88.9%) as a white solid.

Compound 45-2 (12.0 g, 24.79 mmol) was treated with NH₃ in MeOH (200 mL,7 M) at R.T. The solution was stirred at R.T. for 12 h, and thenconcentrated at a low pressure. The residue was purified by columnchromatography (10% MeOH in DCM) to give 45-3 (6.5 g, 95.0%) as a whitesolid.

To a stirred suspension of 45-3 (4.3 g, 15.58 mmol), PPh₃ (8.16 g, 31.15mmol), imidazole (2.11 g, 31.15 mmol) and pyridine (15 mL) in anhydrousTHF (45 mL) was added a solution of I₂ (7.91 g, 31.15 mmol) in THF (100mL) dropwise at 0° C. The mixture was slowly warmed to R.T. and stirredovernight. The mixture was quenched with MeOH (100 mL). The solvent wasremoved at a low pressure, and the residue was re-dissolved in a mixtureof EA and THF (0.2 L, 10:1). The organic phase was washed with sat.Na₂S₂O₃ aq. (2×). The aqueous phase was extracted with a mixture of EAand THF (0.2 L, 10:1, 2×). The concentrated organic phase was dried overanhydrous Na₂SO₄. The residue was purified on a silica gel column (0-10%MeOH in DCM) to afford 45-4 (5.1 g, 85.0%) as a white solid.

Compound 45-4 (800 mg, 2.07 mmol) was dissolved in a mixture of DBU (4mL) and THF (4 mL) at R.T. under N₂. The solution was stirred at R.T.for 1 h. The mixture was neutralized with HOAc, and extracted with amixture of EA and THF (10:1, 40 mL). The organic phase was washed withbrine, and dried over anhydrous Na₂SO₄. The concentrated organic phasewas purified by column chromatography (0-10% MeOH in DCM) to give 45-5(240 mg, 44.9%) as a white solid.

To an ice-cooled solution of 45-5 (1.20 g, 4.65 mmol) in anhydrous MeCN(12 mL) was added NIS (1.57 g, 6.97 mmol) and TEA.3HF (1.12 g, 6.97mmol) under N₂. The mixture was stirred at R.T. for 5 h. The reactionwas quenched with sat. NaHCO₃ solution, and extracted with EA (3×100mL). The organic phase was dried over anhydrous Na₂SO₄, and evaporatedto dryness at low pressure. The residue was purified on a silica gelcolumn (0-5% MeOH in DCM) to give 45-6 (0.91 g, 48.6%) as a white solid.

To a stirred solution of 45-6 (1.2 g, 2.97 mmol) in anhydrous DCM (12mL) was added BzCl (0.83 g, 5.94 mmol), TEA (0.6 g, 5.94 mmol) and DMAP(0.72 g, 5.94 mmol) successively at R.T. The mixture was stirred at R.T.for 12 h. The reaction was quenched with water, and extracted with EA(3×60 mL). The organic phase was concentrated at low pressure. Theresidue was purified by column chromatography (0-5% MeOH in DCM) to give45-7 (1.2 g, 66.2%) as a white solid.

Tetra-butyl ammonium hydroxide (25.78 mL, 51.78 mmol) was neutralizedwith TFA (4.3 mL) to pH=4, and the solution was added to a solution of45-7 (1.09 g, 2.14 mmol) in DCM (30 mL). m-CPBA (1.85 g, 10.74 mmol) wasadded portion-wise under vigorous stirring, and the mixture was stirredfor 12 h. The mixture was diluted with EA (100 mL), and washed with sat.sodium bicarbonate. The organic phase was concentrated at low pressure.The residue was purified by column chromatography (50% EA in PE) to give45-8 (350 mg, 41.1%) as a white solid.

Compound 45-8 (280 mg, 0.704 mmol) was treated with NH₃ in MeOH (10 mL,7 M) at R.T. The mixture was stirred at R.T. for 2 h. The mixture wasconcentrated at a low pressure. The residue was purified by columnchromatography (0-10% MeOH in DCM) to give compound 45 (110 mg, 53.1%)as a white solid. ESI-LCMS: m/z 295.1 [M+H]⁺.

Example 37 Compound 54

To an ice-cooled solution of 54-1 (10 g, 42 mmol) in anhydrous MeCN (200mL) was added TEA.3HF (10 g, 62.5 mmol) and NIS (28 g, 126 mmol). Themixture was stirred at R.T. for 1.5 h, and monitored by LCMS. After thereaction was completed, the mixture was concentrated at a low pressure.The residue was purified by silica gel column chromatography (15% MeCNin DCM) to give 54-2 (12 g, 74%) as a yellow solid.

To a solution of 54-2 (22 g, 57 mmol) in anhydrous DCM (200 mL) wasadded DMAP (21 g, 171 mmol) and BzCl (17.6 g, 125 mol). The mixture wasstirred for 5 h at R.T., and monitored by LCMS. The solution was washedwith sat. NaHCO₃ solution, brine and extracted with EA. The organicphase was dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated at low pressure. The residue was purified by silica gelcolumn chromatography (20% EA in PE) to give 54-3 (30 g, 88%) as a whitefoam.

To a solution of 54-3 (6.5 g, 11 mmol) in anhydrous DMF (270 mL) wasadded NaOBz (15.8 g, 110 mmol) and 15-crown-5 (29 g, 132 mmol). Themixture was stirred at 95° C. for 48 h. The precipitate was removed byfiltration, and the organic solvent was removed at low pressure. Theresidue was dissolved in EA (200 mL), and the solution was washed withsat. NaHCO₃ solution, and brine. The organic layer was dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated at lowpressure. The residue was purified by silica gel column chromatography(20% EA in PE) to give 54-4 (3 g crude, 46.1%) as an oil.

Compound 54-4 (3 g, crude) was treated with NH₃ in MeOH (120 mL, 7 M).The mixture was stirred for 3 h and monitored by TLC. The solution wasconcentrated at low pressure. The residue was purified by silica gelcolumn chromatography (10% isopropanol in DCM) to give 54-5 (1.0 g, 67%)as a white solid. ¹H-NMR (CD₃OD, 400 MHz) δ=1.19 (s, 3H), 3.76-3.82 (m,2H), 4.02 (d, J=19.8 Hz, 1H), 5.70 (d, J=8.07 Hz, 1H), 6.27 (s, 1H),7.89 (d, J=8.07 Hz, 1H).

Compound 54-5 (100 mg, 0.36 mmol) was co-evaporated with toluene 3times. To a stirred solution of 54-5 (100 mg, 0.36 mmol) in a mixture ofMeCN (1.0 mL) and NMI (295 mg, 3.6 mmol) was added a solution of 54-C(255.6 mg, 0.72 mmol, preparation described below) in MeCN (0.5 mL) at0° C. The mixture was stirred at R.T. overnight. The reaction wasquenched with water, and diluted with EA (20 mL). The organic layer waswashed with water and brine. The organic layer was dried over anhydrousNa₂SO₄. The organic phase was concentrated at low pressure. The residuewas purified on a silica gel column (5% i-PrOH in DCM) to give the crudeproduct. The product was purified by prep-HPLC (0.1% HCOOH in water andMeCN) to give compound 54 (46.7 mg, 23.3%) as a white solid. ESI-LCMS:m/z 618 [M+Na]⁺.

To a stirred solution of 54-A (2.0 g, 13.16 mmol) and naphthalen-1-ol(1.89 g, 13.16 mmol) in anhydrous DCM (100 mL) was added a solution ofTEA (1.33 g, 13.16 mmol) in DCM (20 mL) dropwise at −78° C. Afteraddition, the mixture was gradually warmed to R.T., and stirred for 2 h.The solution was cooled to −78° C., and (S)-isopropyl 2-aminopropanoatehydrochloride (2.20 g, 13.16 mmol) in DCM (20 mL) was added, followed byTEA (2.66 g, 26.29 mmol) in DCM (20 mL) dropwise. The mixture wasgradually warmed to R.T., and stirred for 2 h. The organic solvent wasremoved at low pressure. The residue was dissolved in methyl-butylether. The precipitate was filtered, and the filtrate was concentratedat low pressure. The residue was purified on a silica gel column(anhydrous DCM) to give 54-C (1.0 g, 24.8%) as a colorless oil.

Example 38 Compounds 56 and 57

To a solution of 54-5 (300 mg, 1.08 mmol) and NMI (892 mg, 10 mmol) inanhydrous MeCN (4 mL) was added a solution of 57-C (736 mg, 2.17 mmol,preparation described below) in anhydrous MeCN (1 mL) dropwise at 0° C.The mixture was stirred at R.T. overnight. The reaction was quenchedwith water, and diluted with EA (30 mL). The organic layer was washedwith water and brine. The organic phase was dried over anhydrous Na₂SO₄and concentrated at low pressure. The residue was purified by a silicagel column (iPrOH in DCM from 1% to 5%) to give crude compound 56 (276mg, crude). Crude compound 56 (96 mg) was purified by prep-HPLC (0.1%HCOOH in water and MeCN) to give pure compound 56 (46 mg, 47.9%) as awhite solid. ESI-LCMS: m/z 560 [M−F]⁺.

To a solution of compound 56 (180 mg, 0.31 mmol) in anhydrous pyridine(6 mL) was added acetic anhydride (158 mg, 1.54 mmol) dropwise at 0° C.The mixture was stirred at R.T. overnight. The solution was quenchedwith water and concentrated at a low pressure. The residue was dissolvedin EA (10 mL), and washed with brine. The organic layer was dried overanhydrous Na₂SO₄. The organic phase was concentrated at low pressure.The residue was purified by silica gel column (i-PrOH in DCM from 1% to3%) to give crude compound 57 (172 mg). Crude compound 57 was purifiedby prep-HPLC (0.1% HCOOH in water and MeCN) to give pure compound 57 (46mg, 23.8%) as a white solid. ESI-LCMS: m/z 602.3 [M−F]⁺.

Compound 56-C (1.02 g, 23%, a colorless oil) was prepared using aprocedure similar to the preparation of 54-C using 54-A (2.00 g, 13.16mmol) and 4-chlorophenol (1.68 g, 13.16 mmol).

Example 39 Compound 61

Compound 25 (109 mg, 0.39 mmol) and triethylammoniumbis(isopropyloxycarbonyloxymethyl)phosphate (0.6 mmol, prepared from 195mg of bis(isopropyloxycarbonyloxymethyl)phosphate and 85 μL of Et₃N)were rendered anhydrous by coevaporating with pyridine, followed bytoluene. The residue was dissolved in anhydrous THF (3 mL) and cooled inan ice-bath. Diisopropylethyl amine (0.2 mL, 3 eq.), BopCl (190 mg, 2eq.), and 3-nitro-1,2,4-triazole (81 mg, 2 eq.) were added, and themixture was stirred at 0° C. for 90 mins. The mixture was diluted withEtOAc, washed with sat. aq. NaHCO₃ and brine, and dried (Na₂SO₄).Purification on silica gel column with CH₂Cl₂/i-PrOH (4-10% gradient)followed by RP-HPLC purification (A: 0.1% HCOOH in water, B: 0.1% HCOOHin MeCN) yielded compound 61 (28 mg, 12%). ¹H-NMR (CDCl₃): δ 7.24 (d,1H), 6.6 (br, 1H), 5.84 (d, 1H), 5.65-5.73 (m, 4H), 4.94 (m, 2H), 4.38(m, 2H), 4.1 (b, 1H), 2.88 (d, 1H), 1.47 (d, 3H), 1.33 (m, 12H).

Example 40 Compound 74

Dry nucleoside (0.05 mmol) was dissolved in a mixture of PO(OMe)₃ (0.7mL) and pyridine (0.3 mL). The mixture was evaporated in vacuum for 15mins. at 42° C., then cooled to R.T. N-Methylimidazole (0.009 mL, 0.11mmol) was added followed by POCl₃ (0.009 mL, 0.11 mmol). The mixture waskept at R.T. for 20-40 mins and monitored for the formation of compound74 by LCMS. The reaction was quenched with water and isolated by RP HPLCon Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient ofmethanol from 0 to 30% in 50 mM triethylammonium acetate buffer (pH 7.5)was used for elution. The corresponding fractions were combined,concentrated and lyophilized 3 times to remove excess of buffer. MS: m/z396.5 [M−1]⁻.

Example 41 Compound 68

The nucleoside (140 mg, 0.42 mmol) was dissolved in n-butylamine (0.5mL). The mixture was kept for 2 h at R.T., and the amine was thenevaporated. The residue was dissolved in EtOAc, and the organic layerwas washed twice with 10% citric acid, dried over Na₂SO₄, andevaporated. The residue purified by column chromatography on silica gelin linear gradient of methanol in DCM from 0% to 12% over 10 columnvolumes. The fractions containing the product were concentrated andtreated with 80% HCOOH for 1 h at R.T. The mixture was evaporated todryness, and suspended in CH₃CN. The precipitate was separated, washedwith CH₃CN (1 mL) and dried to yield compound 68 (27 mg, 50%). MS: m/z326.5 [M−1]⁻.

Example 42 Compound 62

Compound 45 (30 mg, 0.1 mmol) was dissolved in a mixture of CH₃CN (2 mL)and N-methylimidazole (200 uL). Phosphorochloridate (100 mg, 0.3 mmol)was added, and the mixture was kept for 5 d at R.T. The mixture wasdistributed between water and EA. The organic layer was separated,washed with brine, dried and evaporated. The phosphoroamidate wasisolated by silica gel chromatography in a gradient of methanol in DCMfrom 3% to 10%. The corresponding fractions were concentrated andre-purified by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex).A linear gradient of methanol in DCM from 3% to 95% containing 0.1%formic acid was used for elution. Compound 62 was obtained as a mixtureRp and Rs isomers (9 mg, 16%). MS: m/z 562.1[M−1]⁻.

Example 43 Compound 72

Compound 47 (30 mg, 0.1 mmol) was dissolved in a mixture of CH₃CN (2 mL)and N-methylimidazole (200 uL). Phosphorochloridate (100 mg, 0.3 mmol)was added, and the mixture was kept overnight at 40° C. The temperaturewas increased to 65° C. and heated for 1 h. The mixture was distributedbetween water and EA. The organic layer was separated, washed withbrine, dried and evaporated. The azido-phosphoramidate was purified byRP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A lineargradient of methanol from 30% to 100% in 50 mM triethylammonium acetatebuffer (pH 7.5) was used for elution. The azido-phosphoramidate (8 mg)was dissolved in pyridine/Et₃N (3 mL, 8:1 v/v) and cooled to 0° C. H₂Sgas was bubbled through the solution for 10 min, and the reaction waskept for 1 h at R.T. The solvents were evaporated, and the residueisolated by RP HPLC. The corresponding fractions were combined,concentrated and lyophilized 3 times to remove excess of buffer, toprovide compound 72 (1.2 mg) as mixture Rp and Rs isomers. MS: m/z 544.1[M+1]⁺.

Example 44 Compound 65

To a solution of 65-1 (23.0 g, 39.5 mmol) in anhydrous toluene (200 mL)was added DAST (31.9 g, 198 mmol) dropwise at −78° C., and the solutionwas stirred at −78° C. for 3 h. The mixture was quenched with sat.NaHCO₃, extracted with EA (2×200 mL) and dried over with anhydrousNa₂SO₄. The solution was concentrated to dryness under low pressure. Theresidue was purified on a silica gel column (50% EA in PE) to give 65-2(16.5 g, 71%) as a yellow foam.

A mixture of 65-2 (16.0 g, 27.4 mmol) and NH₄F (3.0 g, 82.2 mmol) inmethanol (100 mL) was stirred at 70° C. for 12 h. The reaction wascooled, and the salt was removed by filtration. The filtrate wasconcentrated to dryness at low pressure. The residue was purified on asilica gel column (3% MeOH in DCM) to give 65-3 (5.1 g, 69.0%) as awhite foam.

To a stirred suspension of 65-3 (4.1 g, 15.2 mmol), PPh₃ (8.0 g, 30.4mmol), imidazole (2.1 g, 30.4 mmol) and pyridine (18.2 mL) in anhydrousTHF (40 mL) was added dropwise a solution of I₂ (5.8 g, 22.8 mmol) inTHF (20 mL) at 0° C. The mixture was stirred at R.T. for 12 h. Thereaction was quenched with MeOH (100 mL), and the solvent was removedunder reduced pressure. The residue was purified on a silica gel column(4% MeOH in DCM) to give pure 65-4 (4.4 g, 77%) as a white solid.ESI-MS: m/z 381.1 [M+1]⁺.

To a stirred solution of 65-4 (2.5 g, 0.7 mmol) in anhydrous THF (3 mL)was added DBU (2.1 g, 14 mmol) at R.T., and the mixture was stirred atR.T. for 1 h. The reaction was quenched with HOAc, and diluted with2-Me-tetrahydrofuran. The solution was washed with brine, dried overwith anhydrous Na₂SO₄ and concentrated to dryness at low pressure. Theresidue was purified on a silica gel column (MeOH 5% in DCM) to give65-5 (1.1 g, 68.9%) as a white foam.

To a stirred solution of 65-5 (800 mg, 3.17 mmol) in anhydrous CH₃CN (10mL) was added TEA.3HF (510 mg, 3.17 mmol) and NIS (785 mg, 3.49 mmol) at0° C. The mixture was stirred for 30 mins, gradually warmed to R.T., andstirred for 1 h. The mixture was quenched with sat. NaHCO₃ solution andNa₂S₂O₃ solution, and extracted with EA (2×20 mL). The organic layer wasdried over with anhydrous Na₂SO₄, and concentrated to dryness at lowpressure. The residue was purified on a silica gel column to give pure65-6 (695 mg, 57.9%) as a yellow solid.

To a stirred solution of 65-6 (650 mg, 1.63 mmol) in pyridine (3 mL) wasadded BzCl (507 mg, 3.59 mmol) at 0° C., and stirred at R.T. for 12 h.The mixture was quenched with water, and concentrated to dryness underreducing pressure. The residue was purified on a silica gel column (EA50% in PE) to yield 65-7 (550 mg, 67%) as a white foam.

Tetra-butylammonium hydroxide (9 mL as 54-56% aqueous solution, 72 mmol)was neutralized with TFA to pH-4 (1.5 mL), and the mixture was added toa solution of 65-7 (375 mg, 0.75 mmol) in DCM (9 mL). m-Chloroperbenzoicacid (924 mg, 60-70%, 3.75 mmol) was added in portions with vigorousstirring, and the mixture was stirred overnight. The mixture was washedwith brine, dried over magnesium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography (EA 50% inPE) to give 65-8 (230 mg, 78.8%) as a white foam. ESI-MS: m/z 393.1[M+1]⁺.

Compound 65-8 (120 mg, 0.24 mmol) was treated with 7N NH₃.MeOH (20 mL),and stirred for 5 h. The mixture was concentrated to dryness at lowpressure. The residue was purified on a silica gel column (propan-2-ol15% in DCM) to yield compound 65 (53 mg, 60.2%) as a white solid.ESI-MS: m/z 288.8 [M+1]⁺.

Example 45 Compound 70

To a solution of 70-1 (3.0 g, 18.0 mmol) and POCl₃ (1.35 g, 9.0 mmol) inDCM (80 mL) was added TEA (3.6 g, 36.0 mmol) in DCM (20 mL) dropwise at0° C. The mixture was stirred at 0° C. for 2 h. A solution ofpentafluorophenol (1.65 g, 9.0 mmol) and TEA (0.9 g, 9.0 mmol) in DCM(20 mL) was added dropwise at 0° C., and the mixture was stirred at 0°C. for 15 h. After the reaction was completed, the mixture wasconcentrated under reduced pressure. The residue was washed by TBME andfiltered. The filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel chromatography (20% EA in PE) to give70-2 (2.7 g, 62.7%) as a white solid. ESI-MS: m/z 491.1 [M+1]⁺.

To a stirred solution of 1-((3 aR,4R,6S,6aS)-6-fluoro-6-(hydroxymethyl)-2-methoxy-3a-methyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrimidine-2,4(1H,3H)-dione (150 mg, 0.47 mmol)in anhydrous THF (2 mL) was added a solution of t-BuMgCl (0.46 mL, 1M inTHF) dropwise at 0° C. The mixture was stirred at R.T. for 40 mins, andre-cooled to 0° C. A solution of 70-2 (462 mg, 0.94 mmol) was added, andthe mixture was stirred at R.T. for 4 h. The mixture was quenched withH₂O, and extracted with EA. The organic layer was dried over Na₂SO₄ andconcentrated under reducing pressure. The residue was purified on asilica gel column (50% EA in PE) to give 70-3 as a white foam (230 mg,78%).

Compound 70-3 (230 mg, 0.37 mmol) was dissolved in 80% HCOOH aqueoussolution (20 mL), and the mixture was stirred at R.T. for 24 h. Thesolvent was removed at low pressure. The residue was purified on asilica gel column to give the crude product, which was purified by RPHPLC (HCOOH system) to give compound 70 as a mixture of two P-isomers(75 mg, 33%). ESI-TOF-MS: m/z 583.0 [M+H]⁺.

Example 46 Compound 75

To a solution of 75-1 (120 g, 0.26 mol) in CH₃CN (2.0 L) was added IBX(109 g, 0.39 mol), and refluxed for 12 h. The reaction was monitored byTLC and LCMS. After cooling to R.T., the mixture was filtered, and thefiltrate was concentrated at low pressure. The crude product was useddirectly for the next step.

Compound 75-2 (130 g, 0.26 mol) was co-evaporated with anhydrous toluenethree times to remove H₂O. To a solution of 75-2 in THF (300 mL) wasadded dropwise vinyl magnesium bromide (700 mL, 0.78 mol, 1N in THF)over 30 min at −78° C. The mixture was stirred for about 1 h at R.T.After the starting material was consumed, the mixture was poured into asat. NH₄Cl solution. The organic layer was washed with brine, dried withanhydrous Na₂SO₄ and filtered. The solution was concentrated at lowpressure to get the crude product. To a solution of this crude product(170 g, 0.346 mol) in anhydrous CH₂Cl₂ was added TEA (105 g, 1.04 mol)and DMAP (84 g, 0.69 mol). Benzoyl chloride (146 g, 1.04 mol) was addedslowly at R.T. for 12 h. The mixture was diluted with CH₂Cl₂ and thenwashed with sat. aq. NaHCO₃. The combined aq. phase was extracted withDCM (100 mL), and the combined organic phase was dried with Na₂SO₄.After filtration, the solution was evaporated to dryness under reducedpressure, and the residue was purified by column chromatography to give75-3 (107 g, 52%).

Uracil (44.8 g, 0.4 mol) (co-evaporated with toluene twice) and NOBSA(81.4 g, 0.4 mol) were dissolved in CH₃CN (500 mL). The mixture wasrefluxed for 1.5 h and then slowly cooled to R.T. The mixture wastreated with 75-3 (59 g, 0.1 mol) and TMSOTf (155 g, 0.7 mol), and thenwarmed to 60-70° C. for 12 h. The mixture was neutralized with a sat.NaHCO₃ solution, and extracted with EA (3×1000 mL). The solution wasdried over anhydrous MgSO4, and evaporated at low pressure. The residuewas purified using a silica gel column to give pure 75-4 (40 g, 69%) asa white solid.

To a solution of 75-4 (50 g, 0.086 mol) in DMF was added PMBCl (16 g,0.1 mol) and K₂CO₃ (17.8 g, 0.13 mol) at 0° C., and the mixture wasstirred at R.T. for 12 h. The mixture was quenched with water (100 mL),and extracted with EA (3×200 mL). The organic phase was concentrated atlow pressure to give crude 75-5 (65 g) which was used in the next stepwithout further purification.

To a solution of crude 75-5 (65 g, 0.086 mol) in MeOH/DCM (4/1) (200 mL)was added NaOMe (16.8 g, 0.3 mol), and the mixture was stirred at R.T.for 2.5 h. The reaction was quenched with dry ice, and then concentratedat low pressure. The residue was dissolved in EA (200 mL) and washedwith brine. The organic layer was concentrated at low pressure, and theresidue was purified using a silica gel column using 1% MeOH in CH₂Cl₂to give 75-6 as a yellow foam (25 g, 75%).

To a solution of 75-6 (25.5 g, 0.065 mol) in DMF was added NaH (10.5 g,0.26 mol) slowly at 0° C., and the mixture was stirred for 30 mins. BnBr(36.3 g, 0.21 mol) was added, and the mixture was stirred at R.T. for 12h. The reaction was quenched with sat. NH₄Cl (aq.), and then extractedwith EA (3×100 mL). The solution was dried over anhydrous MgSO₄, andevaporated at low pressure. The residue was purified by a silica gelcolumn using 10% EA in PE to give 75-7 (20 g, 46%) as a white solid.

To a solution of 75-7 (20 g, 0.03 mol) and NMMO (7 g, 0.06 mol) inTHF:H₂O (5:1) (100 mL) was added OsO₄ (2.6 g, 0.01 mol) at R.T., and themixture was stirred at R.T. for 24 h. The mixture was quenched with asat. Na₂S₂O₃ solution, and extracted with EA (3×100 mL). The organiclayer was washed with brine, and dried over anhydrous MgSO₄. Thesolution was evaporated at low pressure to give the crude compound,which was used in the next step without further purification.

To a solution of the crude diol (0.03 mol) in MeOH:H₂O:THF (170 mL:30mL:50 mL) was added NaIO₄ (9.6 g, 0.045 mol), and the mixture wasstirred at R.T. for 2 h. After filtration, the filtrate was useddirectly in the next step. This solution was treated with NaBH₄ (1.8 g,0.048 mol) at 0° C., and the mixture was stirred at R.T. for 30 mins.The mixture was quenched with MeOH, and evaporated at low pressure. Theresidue was dissolved in EA (100 mL), and washed with brine. Thesolution was evaporated at low pressure, and the residue was purified bya silica gel column using 20% EA in EA to give 75-8 (12 g, 61% overthree steps).

To a solution of 75-8 (14 g, 21 mmol) and DMAP (5.1 g, 42 mmol) in DCM(100 mL) was added MsCl (3.1 g, 27 mmol) at 0° C., and the mixture wasstirred at R.T. for 40 mins. The reaction was quenched with sat. NaHCO₃(aq.), and washed with HCl (0.2 N) solution. The organic phase was driedover anhydrous MgSO₄, and evaporated at low pressure. The residue waspurified by a silica gel column using 5% EA in PE to give mysolateproduct (14 g, 90%). The MsO-product (41 g, 55 mmol) was treated withTBAF (1 N in THF, 500 mL), and the mixture was stirred at 70-80° C. for3 d. The mixture was concentrated at low pressure, and the residue wasdissolved in EA (200 mL). The solution was washed with brine, dried overanhydrous MgSO₄ and evaporated at low pressure. The residue was purifiedby chromatography using 10% EA in PE to give 75-9 (9.9 g, 27%).

To a solution of 75-9 (6.3 g, 9.45 mmol) in CH₃CN:H₂O (3:1, 36 mL:12 mL)was added CAN (15.5 g, 28.3 mmol), and the mixture was stirred at R.T.overnight. The mixture was extracted with EA (3×50 mL). The solution wasdried over anhydrous MgSO₄, and evaporated at low pressure. The residuewas purified by chromatography using 20% EA in PE to give 75-10 (3.6 g,71%) as a white solid.

To a solution of 75-10 (2.4 g, 4.4 mmol) in anhydrous DCM (10 mL) wasadded slowly BCl₃ (1 N, 30 mL CH₂Cl₂) at −70° C., and the mixture wasstirred for 2 h. at −70° C. The mixture was quenched with the slowaddition of MeOH at −70° C., and the mixture was concentrated at lowpressure. The residue was purified by chromatography using 50% EA in PEto give 75-11 (1.2 g, 86%) as a white solid. ESI-MS: m/z 277.1 [M+H]⁺.

To a solution of PPh₃ (3.37 g, 12.8 mmol) in pyridine (15 mL) was addedI₂ (3.06 g, 12 mmol) at 0° C., and the mixture was stirred at R.T. for30-40 mins. The mixture was cooled to 0° C., and then treated with 75-11(2.2 g, 8 mmol) in Py. (5 mL). The mixture was stirred at R.T. under N₂for 12 h. The mixture was quenched with sat. Na₂S₂O₃ (aq.) and extractedwith CH₂Cl₂ (3×50 mL). The organic phase was dried over anhydrous MgSO₄,and then concentrated at low pressure. The residue was purified bychromatography using 1-2% MeOH in CH₂Cl₂ to yield 75-12 (1.8 g, 58%) asa white solid.

To a solution of 75-12 (1.35 g, 3.5 mmol) in THF:CH₃CN (10 mL:5 mL) wasadded DBU (1.06 g, 7 mmol), and the mixture was stirred at 60-70° C. for2 h. The mixture was concentrated at low pressure, and the residue wasdissolved in EA (20 mL). The solution was washed with 10% HCl solutionand brine. The organic phase was dried over anhydrous MgSO₄ andconcentrated at low pressure. The residue was purified by chromatographyusing 30% EA in PE to give 75-13 (0.5 g, 55%).

To a solution of 75-13 (670 mg, 2.6 mmol) in CH₃CN (6 mL) was added NIS(730 mg, 3.25 mmol) and 3HF.TEA (335 mg, 2.1 mmol) at 0° C., and themixture was stirred at R.T. for 2 h. The mixture was quenched with sat.NaHCO₃ (aq.) and Na₂S₂O₃ (aq.) solution. The mixture was extracted withEA (3×20 mL), dried over anhydrous MgSO₄ and concentrated at lowpressure. The residue was purified by chromatography using 1-2% MeOH inCH₂Cl₂ to give 75-14 (1.2 g, 80%).

To a solution of 75-14 (1.0 g, 2.47 mmol), DMAP (0.75 g, 6.2 mmol) andTEA (0.75 g, 7.42 mmol) in DCM (10 mL) was added BzCl (1.15 g, 8.16mmol) in DCM (1 mL) at 0° C., and the mixture was stirred at R.T. for 12h. The mixture was diluted with CH₂Cl₂ (10 mL), and then washed with HCl(0.1 N, 20 mL) solution and brine. The organic phase was dried overanhydrous MgSO₄, and concentrated at low pressure. The residue waspurified by chromatography using 20% EA in PE to afford 75-15 (850 mg,purity-80%).

To a solution of 75-15 (600 mg, 1 mmol) in DMF (25 mL) was added BzONa(1.45 g, 10 mmol), 15-crown-5 (2.2 g, 10 mmol), and the mixture wasstirred at 90-100° C. for 24 h. The mixture was concentrated at lowpressure, and the residue was dissolved in EA (20 mL), and washed withbrine. The organic phase was dried over anhydrous MgSO₄, and thenconcentrated at low pressure. The residue was purified by chromatographyusing 15% EA in PE to give 75-16 (275 mg, 37%) as a light yellow foam.

Compound 75-16 (250 mg, 0.41 mmol) was treated with NH₃.MeOH (7 N, 5mL), and the mixture stirred at R.T. for 15 h. The mixture wasconcentrated at low pressure, and the residue was purified by prep-HPLCto give compound 75 (33 mg, 25%) as a white solid. ESI-MS: m/z 295.1[M+H]⁺.

Example 47 Compound 73

To a solution of IBX (133.33 g, 476 mmol) in dry CH₃CN (2 L) was added73-1 (100.0 g, 216 mol) at R.T. The mixture was refluxed and stirred for12 h. The mixture was filtered, and the filtrate was concentrated at lowpressure to give 73-2 as a yellow oil (90.0 g, 90.4%).

Compound 73-2 (50.0 g, 108.70 mmol) was coevaporated with anhydroustoluene twice to remove H₂O. Ethynyl magnesium bromide, (800 mL, 400.0mmol) was added dropwise into a solution of 73-2 in THF (500 mL) over 20mins at −78° C. The mixture was stirred for about 10 mins at −78° C.When the starting material was consumed, the ice-acetone cooling bathwas removed. The mixture was quenched with a sat. NH₄Cl solution withstirring, and then warmed to R.T. The mixture was extracted with EA,filtered through Celite and washed with brine. The combined organicphase was dried over anhydrous Na₂SO₄, filtered and concentrated at lowpressure to give crude 73-3 as a deep yellow oil (48.0 g, yield: 90.8%).

Compound 73-3 (200.0 g, 411.52 mmol) was dissolved in anhydrous CH₂Cl₂(2000 mL) and then DMAP (100.41 g, 823.05 mmol) and Et₃N (124.94 g, 1.23mol) were added at R.T. The mixture was treated with benzoyl chloride(173.46 g, 1.23 mol) at 0° C. After stirring for 12 h at R.T., thereaction was quenched with H₂O. The combined aq. phase was extractedwith DCM. The combined organic phase was dried over anhydrous Na₂SO₄,filtered and evaporated to dryness under reduced pressure to give ablack oil. The oil was purified by column chromatography using 7%-20% EAin PE as the eluent to give a yellow oil. The residue triturated withCH₃OH and filtered. The filter cake was concentrated in vacuo to give73-4 as a white solid (30.0 g, 36.4%).

Uracil (34.17 g, 305.08 mmol) were coevaporated with anhydrous toluenetwice to remove H₂O. To a stirred suspension of uracil in anhydrous MeCN(150 mL) was added N,O-BSA (123.86 g, 610.17 mmol) at R.T. The mixturewas refluxed for 1.5 h and then cooled to R.T. Compound 73-4 (90 g,152.54 mmol, which were coevaporated with anhydrous toluene twice toremove H₂O) was added. TMSOTf (237.05 g, 1.07 mol) was then added atR.T. The mixture was heated to 70° C., and then stirred overnight andthen monitored by LCMS. The mixture was cooled to R.T., and quenchedwith a sat. NaHCO₃ solution. The solution was extracted with EA. Theorganic layer was dried over Na₂SO₄, and then concentrated at lowpressure. The residue was purified using a silica gel column eluted with10%-50% EA in PE to give 73-5 as a white solid (45 g, 50.9%).

Compound 73-5 (50 g, 86.21 mmol) was treated with NH₃ in MeOH (1 L) atR.T., and then stirred for 48 h. The mixture was concentrated at lowpressure, and the residue was purified by column chromatography (10%MeOH in DCM) to give 73-6 (12.6 g, 54.55%) as a white solid.

To a solution of cyclopentanone (100 g, 1.189 mmol) and trimethylorthoformate (150 mL) in MeOH (600 mL) was added TsOH.H₂O (1.13 g, 5.9mmol), and the mixture was stirred at R.T. for 30 mins. The reaction wasquenched with NaOMe (0.32 g, 5.9 mmol) and H₂O, and the solution wasextracted by n-hexane. The organic layer was dried over anhydrousNa₂SO₄, and then concentrated at low pressure. The cyclopentyl dimethoxyacetal and 73-6 (20 g, 74.63 mmol) was dissolved in DCE (200 mL), andthen treated with TsOH.H₂O (0.71 g, 3.73 mmol). The mixture was stirredat 50° C. for 12 h, and then concentrated at low pressure. The residuewas purified by silica gel column chromatography (1-10% MeOH in DCM) togive 73-7 (15.4 g, 61.8%) as a white solid.

Compound 73-7 (20.0 g, 0.06 mol) was coevaporated with anhydrouspyridine three times to remove H₂O. To an ice-cold solution of 73-7 inanhydrous pyridine (100 ml) was added TsCl (22.8 g, 0.12 mol) at 0° C.,and the mixture was stirred overnight and monitored by LCMS and TLC. Thereaction was quenched with H₂O and extracted with EA. The organic phasewas dried over anhydrous NaSO₄ and evaporated at low pressure. Theresidue was purified by silica gel column chromatography (DCM:MeOH=100:1 to 15:1) to give 78-8 (20.0 g, 69.0%) as a white solid.

To a solution of 73-8 (20.0 g, 0.04 mol) in acetone (200 ml) was addedNaI (31.0 g, 0.2 mol) and heated to reflux overnight and monitored byLCMS. The mixture was quenched with a sat. Na₂S₂O₃ solution, andextracted with EA. The organic phase was dried over anhydrous Na₂SO₄ andevaporated at low pressure. The residue was purified by silica gelcolumn chromatography (DCM: MeOH=100:1 to 15:1) to give 73-9 (15.0 g,83.3%) as a white solid.

To 73-9 (30.0 g, 0.068 mol) in dioxane (60 mL) in sealed tube was addedCuBr (4.9 g, 0.034 mol), i-Pr₂NH (13.6 g, 0.135 mol) and (CH₂O)_(n)(5.1g, 0.17 mol) under N₂. The mixture was heated at reflux for 16 h. Themixture was diluted with EtOAc, and washed with a sat. NH₄Cl solutionand brine. The solution was dried over anhydrous MgSO₄, and concentratedunder reduced pressure. The residue was purified by columnchromatography (DCM: MeOH=100:1 to 15:1) to give 73-10 (10.0 g, 32.3%)as a white solid.

Compound 73-10 (10 g, 21.83 mmol) was treated with HCOOH (80%) in H₂O atR.T. The solution was stirred at 60° C. for 2 h, and then concentratedat a low pressure. The residue was purified by column chromatography(1%-10% MeOH in DCM) to give 73-11 (5.1 g, 58.55%) as a white solid.

Compound 73-11 (5 g, 12.79 mmol) was dissolved in anhydrous MeOH (100mL) and treated with NaOMe (4.83 g, 89.5 mmol) at R.T. The solution wasstirred at 60° C. for 36 h. The mixture was quenched with CO₂ and thenconcentrated at low pressure. The residue was purified by columnchromatography (0-10% MeOH in DCM) to give 73-12 (2.3 g, 68.05%) as ayellow solid. ¹H-NMR (CDCl₃, 400 MHz)=7.29 (d, J=8 Hz 1H), 6.10 (s, 1H),5.71 (d, J=8.0 Hz 1H), 5.18 (t, J=6.4 Hz, 1H), 4.79-4.84 (m, 1H), 4.61(d, J=8.0 Hz, 2H), 4.39 (s, 1H), 3.45 (s, 1H).

To an ice-cold solution of 73-12 (1.5 g, 5.68 mmol) in anhydrous MeCN(15 mL) was added NIS (1.66 g, 7.39 mmol) and TEA.3HF (0.73 g, 4.55mmol) under N₂. The mixture was stirred at R.T. for 1 h. The reactionwas quenched with sat. NaHCO₃ and sat. Na₂SO₃ solution, and extractedwith EA (3×100 mL). The organic phase was dried over anhydrous Na₂SO₄,and evaporated to dryness at low pressure. The residue was purified on asilica gel column (0-5% MeOH in DCM) to give 73-13 (1.08 g, 46.2%) as ayellow solid.

To a stirred solution of 73-13 (1 g, 2.44 mmol) in anhydrous DCM (10 mL)was added DMAP (0.60 g, 4.88 mmol) and Et₃N (0.74 g, 7.32 mmol) at R.T.The mixture was treated with benzoyl chloride (0.79 g, 5.61 mmol) at 0°C. and then stirred at R.T. for 3 h. The reaction was quenched withwater, and extracted with EA (3×60 mL). The organic phase wasconcentrated at low pressure, and the residue was purified by columnchromatography (0-10% MeOH in DCM) to give 73-14 (0.9 g, 59.6%) as awhite solid.

Bu₄NOH (55% in H₂O, 13.74 mL) was treated with TFA (to adjust pH=3-4).The mixture was cooled to R.T. To a solution of 73-14 (0.9 g, 1.46 mmol)in DCM (9 mL) was added m-CPBA (80%, 1.57 g, 7.28 mmol) at R.T. Themixture was stirred at 25° C. for 48 h. The mixture was washed with sat.aq. NaHCO₃. The organic layer was passed through an anhydrous Al₂O₃column, and the solution was concentrated at low pressure. The residuewas purified by a silica gel column (30% EA in PE) to give 73-15 (0.26g, 35.1%) as a yellow solid.

Compound 73-15 (0.25 g, 0.49 mmol) was dissolved in NH₃/MeOH (5 mL, 7M), and the mixture was stirred at R.T. for 24 h under N₂. The mixturewas concentrated at low pressure at R.T., and the residue was purifiedby a silica gel column (5% MeOH in DCM) to give 73-16 (100 g, 67.75%) asa white solid. ¹H-NMR (CD₃OD, 400 MHz)=7.83 (d, J=8 Hz 1H), 6.29 (s,1H), 5.67 (d, J=6.0 Hz 1H), 5.12 (t, J=6.8 Hz, 1H), 4.99-5.01 (m, 1H),4.38 (d, J=19.6 Hz 1H), 3.74-3.81 (m, 2H), 3.35 (s, 1H).

Compound 73-16 (100 mg, 0.33 mmol) was co-evaporated with toluene threetimes to remove H₂O. To a stirred solution of 73-16 (100 mg, 0.33 mmol)in a mixture of MeCN (1.0 mL) and NMI (271 mg, 3.3 mmol) was added asolution of 73-C (216.5 mg, 0.66 mmol) in MeCN (0.5 mL) at 0° C. Themixture was stirred at R.T. overnight and then reaction was quenchedwith water. The mixture was diluted with EA (20 mL), and the organiclayer was washed with water and brine, and dried over anhydrous Na₂SO₄.The organic phase was concentrated at low pressure, and the residue waspurified on a silica gel column (5% i-PrOH in DCM) to give the crudeproduct. The crude product was purified by prep-HPLC (0.1% HCOOH inwater and MeCN) to give compound 73 (35.6 mg, 19.0%) as a white solid.ESI-LCMS: m/z 592 [M+Na]⁺.

To a stirred solution of 73-A (2.0 g, 13.16 mmol) and phenol (1.22 g,13.16 mmol) in anhydrous DCM (100 mL) was added a solution of TEA (1.33g, 13.16 mmol) in DCM (20 mL) dropwise at −78° C. The mixture was warmedgradually to R.T., and then stirred for 2 h. The solution was re-cooledto −78° C., and (S)-isopropyl 2-aminopropanoate hydrochloride (2.20 g,13.16 mmol) in DCM (20 mL) was added, followed by the dropwise additionof TEA (2.66 g, 26.29 mmol) in DCM (20 mL). The mixture was warmedgradually to R.T., and then stirred for 2 h. The organic solvent wasremoved at low pressure, and the residue was dissolved in methyl-butylether. The precipitate was filtered, and the filtrate was concentratedat low pressure. The residue was purified on a silica gel column(anhydrous DCM) to give 73-C (0.9 g, 22.3%) as a colorless oil.

Example 48 Compound 66

Compound 66-2 (2648 g, 7.3 mol) was dissolved in anhydrousdichloromethane (10 L), and the solution was cooled to −40° C. withstirring under N₂. Compound 66-1 (1 kg, 7.69 mol) was dissolved inanhydrous CH₂Cl₂ (3 L) and added to the solution of 66-2 over 30 mins at−40° C. The stirred mixture was allowed to warm to R.T. overnight. Themixture was concentrated under reduced pressure to dryness, and theresidue was suspended in TMBE (6 L). The suspension was filtered toremove Ph₃PO, and the filtrate was concentrated under reduced pressureto afford crude 66-3 (1230 g, 78.6%). ¹H NMR (400 Hz) (CDCl₃): δ 6.65(dt, J=7.6 Hz, 1H), 4.82 (dd, J=14.8, 7.6 Hz, 1H), 4.20-4.10 (m, 3H),3.59 (t, J=8.0 Hz, 1H), 1.86 (d, J=1.2 Hz, 3H), 1.41 (s, 3H), 1.37 (s,3H), 1.26 (t, J=6.8 Hz, 3H).

Crude 66-3 (1230 g, 5.74 mol) was dissolved in acetone (30 L) at 0-5° C.KMnO₄ (1107 g, 5.17 mol) was added in one portion. After being stirredat 0-5° C. for 5 h, the reaction was quenched with sat. aq. sodiumsulfite (20 L). After 30 mins, a colorless suspension was formed. Thesolid was removed by filtration and washed with EA (6 L). The filtratewas extracted with EA (3×2 L). The combined extracts were dried overNa₂SO₄, filtered, and concentrated under reduced pressure to give awhite solid residue. The residue was dissolved in EA, and PE was addedto give a precipitate. The solid was collected by filtration andrecrystallization was 3 times to give 66-4 (770 g, 53.6%) as a whitesolid.

To a stirred solution of 66-4 (770 g, 3.1 mol) in anhydrous DCM (5 L)and triethylamine (1.1 L, 8.05 mol) at 0° C. was added slowly sulfurylchloride (300 mL, 3.6 mmol). The mixture was stirred at R. T. for 2 h,diluted with DCM (3 L), and washed with sat. NaHCO₃ aq. and brine. Theorganic phase was dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by asilica gel column using PE:EA=1:0 to 10:1 as the eluent to give 66-5(490 g, 50.6%) as an oil.

Tetraethylammonium fluoride hydrate (650 g, 3.7 mol) was added into asolution of 66-5 (490 g, 1.6 mol) in anhydrous dioxane (3 L), and themixture was heated to 120° C. for 16 h. The mixture was then cooled toambient temperature. 2,2-Dimethoxypropane (3 L) was added followed byconc. aq hydrochloric acid (200 mL). The mixture was stirred for 3 h atambient temperature. The solvent was concentrated to ⅓ of the originalvolume, and then diluted with EA (3 L). The mixture was washed with coldsat. aq. sodium bicarbonate and brine. The combined aqueous layer wasback-extracted with EA (1 L). The combined organic layer was dried overanhydrous Na₂SO₄, filtered, and concentrated at low pressure to givecrude 66-6 (220 g, 70.8%).

Crude 66-6 (220 g, 0.89 mol) was dissolved in ethanol (2 L) and conc.aq. HCl (60 mL). The solution was stirred at ambient temperature for 48h. and then concentrated under reduced pressure followed byco-evaporations with toluene 3 times to give 66-7 as a pale yellow solid(110 g).

Compound 66-7 (110 g) was dissolved in anhydrous pyridine (1 L). Benzoylchloride (200 mL, 1.67 mol) was added slowly at 0-5° C. The mixture wasstirred at ambient temperature for 45 mins. The reaction was quenchedwith ice and MeOH to form a precipitate. After filtration, the filtratewas washed with MeOH to give 66-8 (200 g, 61.2%) as a white solid.

To a solution of 66-8 (100 g, 269 mmol) in anhydrous THF (1000 ml) wasadded dropwise a solution of lithium tri-tert-butoxyaluminohydride (400ml, 1M, 0.4 mol) at −78° C. under N₂ for 30 mins. The solution wasstirred at −20° C. for 1 h, and TLC (PE: EA=3:1) showed that thereaction was complete. The mixture was quenched with sat.NH₄Cl, anddiluted with EA. After filtration, the filtrate was extracted with EA.The combined layers were dried over Na₂SO₄, and concentrated at lowpressure. The residue was purified by a silica column gel (PE: EA=20:1)to give 66-9 (100 g, 100%) as a colorless oil.

To a stirred solution of PPh₃ (140 g, 382 mol) in CH₂Cl₂ (1000 ml) wasadded 66-9 (100 g, 269 mmol) at −20° C. under N₂. After stirring for 15mins, CBr₄ (177 g, 382 mol) was added dropwise while maintaining thetemperature between −25 and −20° C. under N₂. The mixture was stirredbelow −17° C. for 20 mins. Silica gel was added to the mixture. Themixture was filtered through cold silica column gel and washed with PE:EA (50:1 to 4:1). The combined filtrates were concentrated under reducedpressure at R.T. to give the crude oil product. The residue was purifiedby a silica column gel a second time (PE: EA=50:1 to 4:1) to give 66-10(α-isomer, 64 g, yield: 55%) as a colorless oil.

A mixture of 6-chloro-guanine (55.8 g, 316.5 mol) and t-BuOK (39.5 g,352.7 mmol) in t-BuOH (500 mL) and MeCN (280 mL) was stirred for 30mins. Compound 66-10 (48 g, 105.5 mmol) was added at R.T., and themixture was heated to 50° C. and stirred overnight. The reaction wasmonitored by TLC (PE:EA=2:1). The mixture was quenched with solid NH₄Cl.After stirring for 1 h, the mixture was filtered and washed with MeCN.The filtrate was evaporated at low pressure, and the residue waspurified by a silica gel column to give 66-11 (33 g, 57%).

To a solution of 66-11 (49 g, 93.1 mol) in CH₂Cl₂ (200 mL) was addedAgNO₃ (31.7 g, 186 mmol), collidine (22.5 g, 186 mmol) and MMTrCl (43 g,140 mmol) in small portions under N₂ at 0° C. The mixture was stirred atR.T., and monitored by TLC (PE:EA=4:1). After filtration, the organicphase was washed with NaHCO₃ aqueous and brine. The organic layer wasdried over anhydrous Na₂SO₄ and concentrated at low pressure. Theresidue was purified by a silica gel column (PE:ME=20:1 to 1:1) to give66-12 (70 g, 94.2%).

Sodium (10.1 g, 439 mmol) was dissolved in dry EtOH (600 mL) at 70° C.and then cooled to 0° C. To a solution of 66-12 (70 g, 87.7 mmol) wasadded a freshly prepared NaOEt solution in portions at 0° C., and themixture was stirred for 1 h. at R.T. After TLC and LCMS showed thereaction was completed, the reaction was quenched with carbon dioxide.The mixture was evaporated at low pressure, and the residue was purifiedusing silica gel column chromatography (DCM: MeOH=100:1 to 20:1) to give66-13 (50 g, yield 5%) as a yellow solid.

A mixture of PPh₃ (35 g, 133.5 mol) and I₂ (31.75 g, 125 mmol) inanhydrous pyridine (600 mL) was stirred for 30 mins, and then a solutionof 66-13 (50 g, 83.3 mmol) in pyridine (100 mL) was added at 0° C. Themixture was stirred overnight at R.T. and monitored by TLC(DCM:MeOH=50:1). The reaction was quenched with a sat. NaHCO₃ solution,and extracted with DCM (3×50 mL). The organic phase was dried overanhydrous MgSO₄, and evaporated at low pressure. The residue waspurified using silica gel column chromatography (DCM: MeOH=200:1 to50:1) to give 66-14 (50 g, 84.7%).

To a solution of 66-14 (37 g, 52.1 mmol) in dry THF (400 mL) was addedDBU (16 g, 105 mmol). The mixture was heated to reflux and stirred for 3h. The reaction was monitored by LCMS. The reaction was quenched with asat. NaHCO₃ solution, and extracted with EA. The combined organic layerswere dried over anhydrous Na₂SO₄, and evaporated at low pressure. Theresidue was purified using silica gel column chromatography (PE:EA=10:1to 5:1) to give 66-15 (25 g, 61.1%) as a white solid.

To an ice-cold solution of 66-15 (26 g, 44.6 mmol) in dry MeCN (300 mL)was added NIS (12.68 g, 56 mmol) and NEt₃.3HF (10.6 g, 67 mmol) at 0° C.The reaction was stirred at R.T. for 2 h. and monitored by LCMS. Afterthe reaction was completed, the reaction was quenched with a sat Na₂SO₃and sat. NaHCO₃ solution, and extracted with EA. The organic layer wasseparated, dried over anhydrous Na₂SO₄, and evaporated at low pressure.The residue was purified using silica gel column chromatography (PE:EA=8:1 to 1:1) to give 66-16 (21 g, 64.4%) as a white solid.

To a solution of 66-16 (21 g, 28.8 mol) in CH₂Cl₂ (150 mL) was addedAgNO₃ (9.8 g, 59.6 mmol) and collidine (7 g, 59.8 mmol) and MMTrCl (13.1g, 42.5 mmol) in small portions under N₂ at 0° C. The mixture wasstirred at R.T., and the reaction was monitored by TLC (PE:EA=2:1).After filtration, the solution was washed with sat. aq. NaHCO₃ andbrine. The organic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated at low pressure. The residue was purified by a silica gelcolumn to give 66-17 (25 g, yield 86.5%).

To a solution of 66-17 (22 g, 22 mmol) in dry DMF (500 mL) was addedNaOBz (31.9 g, 220 mmol) and 15-crown-5 (48.4 g, 220 mmol), and themixture was stirred for 72 h. at 95° C. The mixture was diluted with EA,washed with water and brine, and dried over MgSO₄. The organic layer wasevaporated at low pressure, and the residue was purified using a silicagel column chromatography to give 66-18 (15 g, 68.8%) as a white solid.

Compound 66-18 (15.2 g, 15.3 mmol) was co-evaporated with anhydroustoluene 3 times to remove H₂O. The compound was treated with NH₃ in MeOH(7 N, 200 mL) at R.T. The mixture was stirred for 18 h at R.T., and thereaction was monitored by LCMS. The residue was concentrated at lowpressure, and purified using silica gel column chromatography to give66-19 (11 g, 81%) as a white solid.

To a stirred solution of 66-20 (14 g, 15.73 mmol) in anhydrous CH₃CN(150 mL) was added N-methylimidazole (23.5 g, 283.9 mmol) at 0 to 5° C.(ice/water bath) followed by a solution ofphenyl(cyclohexanoxy-L-alaninyl)phosphorochloridate (16.33 g, 47.2 mmol,dissolved in 50 mL of CH₃CN). The solution was stirred at 0 to 5° C. for12 h and then diluted with EA. The solution was washed 50% aqueouscitric acid solution and brine. The organic layer was separated, driedover anhydrous MgSO₄ and filtered. The filtrate was concentrated at lowpressure, and the residue was purified on silica gel with PE: EA=5:1 asthe eluent to give 66-20 (17.62 g, 93.4%) as a white solid.

Compound 66-20 (17.62 g, 14.7 mmol) was dissolved in 80% AcOH (200 mL),and the mixture was stirred overnight at R.T. After removal of thesolvents, the reside was purified on silica gel using PE:EA=2:1 toeluent to give the crude product, which was purified on viareverse-phase HPLC using acetonitrile and water to give compound 66(5.25 g, yield 66%) as a white solid. ESI-LCMS: m/z 655 [M+H]⁺.

Example 49 Compound 67

To a solution of the nucleoside (300 mg, 1.09 mmol) and proton-sponge(467 mg, 2.18 mmol) in anhydrous CH₃CN (5 mL) at 0° C. under N₂ wasadded dropwise a solution of phosphorus oxychloride (330 mg, 2.18 mmol)in anhydrous CH₃CN (1 mL). The mixture was stirred at 0° C. for 30 mins,and the hydrogen chloride salt of (S)-ethyl 2-aminopropanoate (998 mg,6.52 mmol) and triethylamine (1.5 mL, 10.87 mmol) at 0° C. were added.The mixture was stirred overnight at 30° C. The reaction was quenchedwith water, and extracted with EA (3×20 mL). The organic layer wasconcentrated at low pressure, and the residue was purified by reversephase HPLC to give compound 67 (20 mg, 3%) as a white solid. ESI-LCMS:m/z 535 [M−F]⁺.

Example 50 Compound 59

To a solution of sodium hydrosulfide (4.26 g, 76.0 mmol) in EtOH (100mL) was added t-butyryl chloride (76.2 mmol; 9.35 mL) dropwise at 0° C.,and the mixture was stirred at R.T. for 1 h. A solution of2-(2-chloroethoxy)ethanol (57 mmol; 6.0 mL) and TEA (21 mL, 120 mmol)was added, and the mixture was heated at reflux for 60 h. The mixturewas filtered, and then concentrated to a small volume. The residue wasdissolved in EA, and then washed with water, sat. aq. NaHCO₃ and brine.The organic phase was dried over Na₂SO₄, filtered and concentrated invacuo. The crude product (10.0 g) was isolated and 5 grams were purifiedby silica gel flash column chromatography using a gradient of 0 to 100%EA in hexane to give 59-3 (4.5 g, 22 mmol) as a clear, colorless oil.¹H-NMR (CDCl₃): 3.70-3.74 (m, 2H), 3.5-3.65 (m, 4H), 3.1 (t, 2H), 1.25(s, 9H).

A solution 59-3 (4.5 g; 21.8 mmol) and triethylamine (6.7 mL, 87.2 mmol)in tetrahydrofuran (50 mL) was added dropwise over 1 h to a stirredsolution of N,N-diisopropylphosphorodichloridite (2.0 mL, 10.9 mmol) inTHF (50 mL) under argon at −78° C. The mixture was stirred at R.T. for 2h, and then diluted with EA (200 mL). The mixture was washed with sat.aq. NaCl and dried over Na₂SO₄. After filtration, the filtrate wasevaporated under reduced pressure to give a pale yellow oil.Purification by flash column chromatography using a gradient of EA(0-5%) in hexane containing 5% triethylamine afforded 59-4 (2.5 g, 4.25mmol) as a clear, colorless oil. ¹H-NMR (CDCl₃): 3.70-3.82 (m, 4H),3.57-3.65 (m, 10H), 3.1 (t, 4H), 1.25 (s, 18H), 1.17 (t, 12H); ³¹P-NMR(CDCl₃): 148.0 ppm.

Compound 59-5 (285 mg, 0.9 mmol) and DCI (175 mg, 1.5 mmol) werecoevaporated twice with ACN and then dissolved in ACN (5 mL). Compound59-4 (790 mg, 1.35 mmol) in ACN (4 mL) was added, and the reaction wasmonitored by TLC. After 15 mins, tert-butylhydroperoxide (0.5 mL of 5.5Msolution in decane) was added, and the mixture was stirred for 10 mins.The mixture was diluted with EA (25 mL), washed with sat. aq. NaHCO₃ andsat. aq. NaCl solution, dried over Na₂SO₄, filtered and concentrated.Purification by flash column chromatography using a gradient of EA(0-100%) in hexane afforded 59-6 (0.17 g, 0.22 mmol) as a white solid.Compound 59-6 was dissolved in 80% aq. HCOOH (5 mL). After 30 mins atR.T., the solvent was removed and coevaporated twice with toluene. Theresidue was dissolved in methanol (10 mL) and TEA (0.2 mL) was added.After 2 mins at R.T., the solvent was removed in vacuo. Purification byflash column chromatography using a gradient of methanol (0-15%) in DCMafforded compound 59 (90 mg). ¹H-NMR (CDCl₃): 7.40 (d, 1H), 6.1 (s, 1H),5.83 (d, 1H), 4.3 (t, 2H), 4.1-4.2 (m, 6H), 3.70-3.82 (m, 4H), 3.57-3.65(m, 4H), 3.1 (t, 4H) 1.61 (s, 8H), 1.3 (s, 3H), 1.23 (s, 18H). ³¹P-NMR(CDCl₃): −1.55 ppm.

Example 51 Compound 60

Compound 60-1 (6.0 g, 31.6 mmol) was prepared using a similar procedureto the one used to prepared 59-3 using 4-chlorobutanol. Compound 60-1was obtained as a clear, colorless oil. ¹H-NMR (CDCl₃): 3.67 (s, 2H),2.86 (m, 2H), 1.65 (m, 4H), 1.25 (s, 9H).

Compound 60-2 (2.14 g, 4.0 mmol) was prepared using a similar procedureto the one used to prepared 59-4. Compound 60-2 was obtained as a clear,colorless oil. ¹H-NMR (CDCl₃): 3.67 (m, 6H), 2.86 (t, 4H), 1.65 (m, 8H),1.25 (s, 18H), 1.17 (t, 12H). ³¹P-NMR (CDCl₃): 143.7 ppm.

Compound 60-3 (0.23 g, 0.22 mmol) was prepared using a similar procedureto the one used to prepared 59-6 using 59-5 and 60-2. Compound 60-3 wasobtained as a white solid. Using a similar procedure to the one used toprepared compound 59, 60-3 was used to prepare compound 60 (170 mg).¹H-NMR (CDCl₃): 7.40 (d, 1H), 6.1 (s, 1H), 5.83 (d, 1H), 4.3 (t, 2H),4.1-4.2 (m, 6H), 2.8 (t, 4H), 1.78 (m, 4H), 1.69 (s, 8H), 1.3 (s, 3H),1.23 (s, 18H). ³¹P-NMR (CDCl₃): −1.56 ppm.

Example 52 Compound 58

Compound 58-1 was prepared according to the procedure described inLefebre et al. J. Med. Chem. (1995) 38:3941-3950, which is herebyincorporated by reference for the limited purpose of its description ofthe preparation of 58-1.

Compound 58-2 (0.33 g, 0.5 mmol) was prepared using a similar procedureto the one used to prepared 59-6 using 59-5 and 58-1. Compound 58-2 wasobtained as a white solid. Using a similar procedure to the one used toprepared compound 59, 58-2 was used to prepare compound 58 (130 mg).¹H-NMR (CDCl₃): 7.40 (d, 1H), 6.1 (s, 1H), 5.83 (d, 1H), 4.3 (t, 2H),4.1-4.2 (m, 6H), 3.2 (t, 4H), 1.69 (s, 4H), 1.3 (s, 3H), 1.23 (s, 18H);³¹P-NMR (CDCl₃): −2.4 ppm.

Example 53 Compound 47

Compound 47-1 (1.0 g, 3.53 mmol) was coevaporated with anhydrouspyridine 3 times to remove H₂O. To an ice-cold solution of 47-1 inanhydrous pyridine (9 mL) was added TsCl (808 mg, 4.24 mmol) in pyridine(3 mL) drop-wise at 0° C., and the mixture was stirred for 18 h. at 0°C. The reaction was monitored by LCMS, and then quenched with H₂O. Afterconcentration at low pressure, the residue was dissolved in EA (50 mL).The solution was washed with sat. NaHCO₃ solution and brine. The organiclayer was dried over anhydrous Na₂SO₄ and filtered. The filtrate wasevaporated at low pressure, and the residue was purified by silica gelcolumn chromatography (1% MeOH in DCM) to give 47-2 (980 mg, 63%) as awhite solid.

To a solution of 47-2 (980 mg, 2.24 mmol) in acetone (10 mL) was addedNaI (1.01 g, 6.73 mmol), and the mixture was heated to reflux overnight.The reaction was monitored by LCMS. After the reaction was completed,the mixture was concentrated at low pressure. The residue was dissolvedin EA (50 mL). The solution was washed with brine, and dried overanhydrous Na₂SO₄. The solution was evaporated at low pressure, and theresidue was purified by silica gel column chromatography (1% MeOH inDCM) to give 47-3 (700 mg, 79%) as a solid.

To a solution of 47-3 (700 mg, 1.78 mmol) in dry THF (9 mL) was addedDBU (817 mg, 5.34 mmol), and the mixture was heated to 60° C. Themixture was stirred overnight, and monitored by LCMS. The reaction wasquenched with sat. NaHCO₃ and extracted with EA (3×50 mL). The organicphase was dried over anhydrous Na₂SO₄, and filtered. The filtrate wasevaporated at low pressure, and the residue was purified by silica gelcolumn chromatography (1% MeOH in DCM) to give 47-4 (250 mg, 53%) as awhite solid.

To an ice-clod solution of 47-4 (250 mg, 0.94 mmol) in dry MeCN (5 mL)was added NEt₃.3HF (151 mg, 0.94 mmol) and NIS (255 mg, 1.13 mmol). Themixture was stirred at R.T., for 3 h., and checked by LCMS. The reactionwas quenched with sat Na₂S₂O₃ and sat. NaHCO₃ solution, and extractedwith EA (3×50 mL). The organic layer was separated, dried over anhydrousNa₂SO₄, and evaporated at low pressure. The residue was purified bysilica gel column chromatography (2% acetone in DCM) to give 47-5 (170mg, 44%).

To a solution of 47-5 (270 mg, 0.65 mmol) in dry DCM (4 mL) was addedDMAP (158.6 mg, 1.3 mmol), and BzCl (137 mg, 0.98 mmol). The mixture wasstirred for 4-5 h. at R.T., and checked by LCMS. The mixture was dilutedwith CH₂Cl₂, and washed with sat. NaHCO₃ solution and brine. The organiclayer was evaporated at low pressure, and the residue was purified bysilica gel column chromatography (20% EA in PE) to give 47-6 (290 mg,86%) as a solid.

To a solution of 47-6 (900 mg, 1.74 mmol) in dry DMF (45 mL) was addedNaOBz (2.5 g, 17.4 mmol) and 15-crown-5 (4.5 g, 20.9 mmol). The mixturewas stirred for 48 h at 90-100° C. The mixture was diluted with EA (100mL), and washed with brine. The organic layer was evaporated at lowpressure, and the residue was purified by silica gel columnchromatography (20% EA in PE) to give 47-7 (500 mg, 56%) as a solid.

To a solution of 47-7 (500 mg, 0.98 mmol) in anhydrous CH₃CN (5 mL) wasadded TPSCl (741 mg, 2.45 mmol), DMAP (299.6 mg, 2.45 mmol) and NEt₃(248 mg, 2.45 mmol) at R.T., and the mixture was stirred overnight. Themixture was then treated with NH₃ in THF (5 mL) and then stirred foranother 30 mins. The mixture was diluted with EA (100 mL). The solutionwas washed with 0.5% AcOH solution. The organic solvent was dried overanhydrous MgSO4, and concentrated at low pressure. The crude product waspurified by silica gel column chromatography (2% Acetone in DCM) to give47-8 (257 mg, 51.6%) as a white solid. ESI-MS: m/z 509 [M+H]⁺.

Compound 47-8 (80 mg, 0.16 mmol) was dissolved in n-butylamine (3 mL).The mixture was kept overnight at R.T. and evaporated. The residue wascrystallized from methanol to give compound 47 (30 mg). The motherliquor was purified by RP HPLC on Synergy 4 micron Hydro-RP column(Phenominex). A linear gradient of methanol from 0 to 30% in 50 mMtriethylammonium acetate buffer (pH 7.5) was used for elution. Thecorresponding fractions were combined, concentrated and lyophilized 3times to remove excess of buffer to yield additional compound 47 (13mg). Compound 47 (total yield 43 mg, 73%). MS: m/z 299.7 [M−1]⁻.

Example 54 Compound 83

To a stirred solution of POCl₃ (2.0 g, 13 mmol) in anhydrous DCM (10 mL)was added 1-naphthol (1.88 g, 13 mmol) at −70° C., and TEA (1.31 g, 13mmol) in DCM (3 mL) dropwise at −70° C. The mixture was gradually warmedto R.T. and stirred for 1 h. Crude 83-1 was obtained.

To a stirred solution of (S)-isopropyl 2-aminopropanoate hydrochloride(2.17 g, 13 mmol) in DCM (10 mL) was added crude 83-1 at −70° C. TEA(2.63 g, 26 mmol) was added to the stirred solution dropwise at −70° C.The mixture was gradually warmed to R.T. and stirred for 2 h. Thereaction was monitored by LCMS and quenched with n-propylamine. Themixture was concentrated at low pressure, and the residue was purifiedby a silica gel column (PE:MTBE=5:1˜1:1) to give pure 83-2 (1.6 g, 35%).

To a solution of 83-(A) (300 mg, 0.337 mmol) and NMI (276 mg, 3.37 mmol)in anhydrous CH₃CN (4 mL) was added 83-2 (240 mg, 0.674 mol, in DCM (5mL)) at 0° C. The mixture was stirred at R.T. for 10 h. The reaction wasmonitored by LCMS. The reaction was quenched with water, and extractedwith CH₂Cl₂ (3×20 mL). The organic phase was dried over anhydrous MgSO4,and concentrated at low pressure. The residue was purified by sil-gel(PE:EA=5:1˜2:1) to give 83-3 (380 mg, 93%).

Compound 83-3 (380 mg, 0.314 mmol) was dissolved in CH₃COOH (80%, 8 mL),and stirred at 40-50° C. for 2.5 h. The reaction was monitored by LCMS.The mixture was concentrated at low pressure, and the residue waspurified by chromatography (PE:EA=1:1˜EA) to give crude compound 83. Thecrude product was purified by prep-HPLC (neutral system, NH₄HCO₃) togive pure compound 83 (70 mg, 80%) as a white solid. ESI-MS: m/z 665.1[M+H]⁺.

Example 55 Compound 79

A solution of 79-1 (16.70 g, 0.363 mol) and TEA (36.66 g, 0.363 mol) inCH₂Cl₂ (150 mL) was added dropwise to a stirred solution of POCl₃ (55.65g, 0.363 mol) in DCM (100 mL) over 25 mins at −78° C. After the mixturewas stirred for 2 h. at R.T., the triethylamine hydrochloride salt wasfiltered, and washed with CH₂Cl₂ (100 mL). The filtrate was concentratedat low pressure, and the residue was distilled under high vacuum (˜10 mmHg) with a cow-head fraction collector. The product was collectedbetween 45° C. (distillation head temperature) as a colorless liquid(30.5 g, 50% yield). ¹H-NMR (400 MHz, CDCl₃) δ=4.44 (dq, J=10.85, 7.17Hz, 2H), 1.44-1.57 (m, 3H); ³¹P-NMR (162 MHz, CDCl₃) δ=6.75 (br. s.,1P).

To a stirred suspension of 83-A (93 mg, 0.15 mmol) in CH₂Cl₂ (1 mL) wasadded TEA (61 mg, 0.15 mmol) at R.T. The mixture was cooled to −20° C.,and then was treated with a 79-2 (35 mg, 0.21 mmol) solution dropwiseover a period of 10 mins. The mixture was stirred at this temperaturefor 15 min., and then was treated with NMI (27 mg, 0.33 mmol). Themixture was stirred at −20° C., and then slowly warmed to R.T. Themixture was stirred overnight. The mixture was suspended in EA (15 mL),washed with brine (10 mL) and dried over anhydrous sodium sulfate. Thesolution was concentrated at low pressure, and the residue was purifiedby chromatography (DCM: MeOH=100:1) to give 79-3 (60 mg, yield: 56%) asa solid.

A solution of 79-3 (60 mg, 0.085 mmol) in 80% AcOH aqueous (2 mL) wasstirred at R.T. for 2 h. The mixture was concentrated under reducedpressure, and the residue was purified by a silica gel column elutingDCM/MeOH=50/1 and prep-HPLC to give compound 79 (23 mg, 62%) as a whitesolid. ESI-MS: m/z 436.3 [M+H]⁺.

Example 56 Compound 80

Compound 80-2 was prepared using a similar procedure as for thepreparation of 79-2 using a solution of iso-butanol (23.9 g, 322.98mmol) and POCl₃ (49.5 g, 322.98 mmol). Compound 80-2 (26 g, 42% yield)was obtained as a colorless liquid. ¹H-NMR (400 MHz, CDCl₃) δ=4.10 (dd,J=9.04, 6.39 Hz, 2H), 2.09 (dq, J=13.24, 6.67, 6.67, 6.67, 6.67 Hz, 1H),1.01 (d, J=6.62 Hz, 6H); ³¹P-NMR (162 MHz, CDCl₃) δ=7.06 (br. s., 1P).

To a stirred suspension of 83-A (310 mg, 0.5 mmol) in CH₂Cl₂ (3 mL) wasadded TEA (202 mg, 2 mmol) at R.T. The mixture was cooled to −20° C.,and then was treated with 80-2 (134 mg, 0.7 mmol). The mixture wasstirred at this temperature for 15 mins and then was treated with NMI(90 mg, 1.1 mmol). The mixture was stirred at −20° C. for 1 h., and thenslowly warmed to R.T. overnight. The mixture was suspended in EA (15mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate.The organic phase was concentrated at low pressure, and the residue waspurified by silica column gel (DCM: MeOH=100:1) to give 80-3 (310 mg,yield: 84%) as a solid.

A solution of 80-3 (310 mg, 0.43 mmol) in 80% AcOH aqueous (4 mL) wasstirred at R.T. for 2 h. The mixture was concentrated at low pressure,and the residue was purified by a silica gel column elutingDCM/MeOH=50/1 and prep-HPLC to give compound 80 (79 mg, 50%) as a whitesolid. ESI-MS: m/z 464.0 [M+H]⁺.

Example 57 Compound 81

Compound 81-2 was prepared using a similar procedure as for thepreparation of 79-2 using a solution of isopropyl alcohol (21 g, 350mmol) and POCl₃ (53.6 g, 350 mmol). Compound 81-2 (40.5 g, 65% yield)was obtained as a colorless liquid. ¹H-NMR (400 MHz, CDCl₃) δ=4.94-5.10(m, 1H), 1.48 (d, J=6.17 Hz, 6H); ³¹P-NMR (162 MHz, CDCl₃) δ=5.58 (br.s., 1P).

Compound 81-3 was prepared using a similar procedure as for thepreparation of 80-3 using 81-2 (124 mg, 0.7 mmol) and 83-A (310 mg, 0.5mmol). Compound 81-3 (300 mg, 83%) was obtained as a solid.

Compound 81 was prepared using a similar procedure as for thepreparation of compound 80 using 81-3 (300 mg, 0.41 mmol) in 80% AcOHaqueous (4 mL). Compound 81 (80 mg, 43%) was obtained as a white solid.ESI-MS: m/z 450.0 [M+H]⁺.

Example 58 Compound 82

To an ice cooled solution of 82-1 (50 g, 204.9 mmol) in dry Py (400 mL)was added TIPDSCl (70.78 g, 225.4 mmol) dropwise. The mixture wasstirred at R.T. for 16 h, and then concentrated at low pressure. Theresidue was purified by chromatography using 20% EA in PE to generate82-2 (111.5 g, 100%) as a white solid.

To a solution of 82-2 (50 g, 103 mmol) in anhydrous CH₃CN (400 mL) wasadded IBX (43 g, 153 mmol) at R.T. The mixture was refluxed overnightand monitored by TLC (PE:EA=1:1). The precipitate was filtered off, andthe filtrate was concentrated to give the crude 82-3 (50 g, 99%) as awhite solid.

To a solution of trimethylsilylacetylene (20 g, 200 mmol) in anhydrousTHF (400 mL) was added dropwise n-BuLi (80 mL, 200 mL) at −78° C. Themixture was stirred at −78° C. for 30 mins, and then warmed to R.T for10 mins. Compound 82-3 (30 g, 60 mmol) in THF (100 mL) was added to themixture dropwise at −78° C. The mixture was stirred at −78° C. for 1 hand then slowly warmed to R.T. The mixture was stirred for 20 mins, andthen the reaction was quenched with a sat. NH₄Cl solution at −78° C. Themixture was diluted with EA. The organic phase was washed with brine,dried over anhydrous Na₂SO₄, and concentrated at low pressure. Theresidue was purified by silica gel column chromatography (15% EA in PE)to give 82-4 as a white solid (14 g, 50%).

Compound 82-4 (14 g, 24 mmol) was dissolved in anhydrous toluene (100mL) under N₂ and cooled to −78° C. DAST (19 g, 120 mmol) was addeddropwise at −78° C. and stirring was continued for 1.5 h. The mixturewas diluted with EA and poured into a sat. NaHCO₃ solution. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated at low pressure. The residue was purified by silica gelchromatography (20% EA in PE) to give 82-5 as a white solid (12 g, 81%).

A mixture of 82-5 (12 g, 20 mmol) and NH₄F (11 g, 30 mmol) in MeOH (150mL) was refluxed for 2 h. After cooling to R.T, the mixture wasconcentrated at low pressure, and the residue was purified by silica gelcolumn chromatography (5% MeOH in DCM) to give 82-6 (3.1 g, 58%) as awhite solid.

To a solution of 82-6 (3.1 g, 11.6 mmol) in dry Py (50 mL) was addedimidazole (3.1 g, 46.4 mmol) and TBSCl (5.2 g, 34.8 mmol). The mixturewas stirred at 50-60° C. for 3 h. The mixture was concentrated at lowpressure, and the residue was dissolved in EA (100 mL). The solution waswashed with brine, dried over anhydrous Na₂SO₄, and concentrated at lowpressure. The residue was purified by silica gel chromatography (20% EAin PE) to give 82-7 as a white solid (5 g, 86%).

To a solution of 82-7 (4.5 g, 9 mmol) in 1,4-dioxane (45 mL) was addedCuBr (643 mg, 4.5 mmol), dicyclohexylamine (3.3 g, 18 mmol) andparaformaldehyde (675 mg, 22.5 mmol). The mixture was refluxed for 24 hand then cooled to R.T. The reaction was quenched with a sat. NH₄Clsolution. The mixture was extracted with EA (3×100 mL). The organiclayer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated at low pressure. The residue was purified by silica gelcolumn chromatography (15% EA in PE) to give 82-8 as a white solid (2.0g, 43%).

A mixture of 82-8 (2 g, 4 mmol) and NH₄F (2.2 g, 60 mmol) in MeOH (20mL) was refluxed overnight. After cooling to R.T., the mixture wasconcentrated at low pressure, and the residue was purified by silica gelcolumn chromatography (5% MeOH in DCM) to give 82-9 (946 mg, 83%) as awhite solid.

To a stirred suspension of 82-9 (946 mg, 3.33 mmol), PPh₃ (1.3 g, 5mmol), imidazole (453 mg, 6.66 mmol) and pyridine (3 mL) in anhydrousTHF (12 mL) was added a solution of I₂ (1 g, 4.33 mmol) in THF (4 mL)dropwise at 0° C. The mixture was warmed to R.T. and stirred for 16 h.The reaction was quenched with a sat. Na₂S₂O₃ aq. solution and extractedwith EA (3×60 mL). The organic layer was dried over Na₂SO₄ andconcentrated at low pressure. The residue was purified on a silica gelcolumn (2% MeOH in DCM to 5% MeOH in DCM) to afford 82-10 (2.1 g, crude)as a white solid.

To a solution of 82-10 (2.1 g, 5.3 mmol) in THF (15 mL) was added DBU(15 g, 100 mmol) and the mixture stirred for 30 mins. The mixture wasdiluted with EA and neutralized with acetic acid. The solution waswashed with brine, dried over anhydrous Na₂SO₄, and concentrated at lowpressure. The residue was purified by silica gel column chromatography(1.5% MeOH in DCM) to give 82-11 as a white solid (800 mg, 90%).

To an ice-cooled solution of 82-11 (800 mg, 3 mmol) in dry MeCN (1.5 mL)was added NEt₃.3HF (484 mg, 3 mmol) and NIS (1.68 g, 7.5 mmol). Themixture was stirred at R.T. for 30 mins., and the reaction was monitoredby LCMS. The reaction was quenched with sat. Na₂S₂O₃ and sat. NaHCO₃solution, and extracted with EA (3×50 mL). The organic layer was driedover anhydrous Na₂SO₄, and concentrated at low pressure. The residue waspurified by a silica gel column (25% EA in PE) to afford 82-12 (850 mg,68%) as a white solid.

To a solution of 82-12 (850 mg, 2 mmol) in dry DCM (10 mL) was addedDMAP (488 mg, 4 mmol) and BzCl (422 mg, 3 mol). The mixture was stirredfor 4-5 h at R.T., and the reaction was monitored by LCMS. The mixturewas diluted with CH₂Cl₂ (40 mL), and washed with a sat. NaHCO₃ solution.The organic layer was dried over anhydrous Na₂SO₄, and filtered. Thefiltrate was evaporated at low pressure, and the residue was purified bysilica gel column chromatography (20% EA in PE) to give 82-13 (900 mg,87%) as a white foam.

Tetra-butylammonium hydroxide (21 mL as 54-56% aqueous solution, 42mmol, 24 eq.) was adjusted with TFA to pH ˜4 (˜3.5 mL), and the solutionwas treated with a solution of 82-13 (900 mg, 1.7 mmol) in DCM (21 mL).m-Cloroperbenzoic acid (2.1 g, 60-70%, ˜8.75 mmol, ˜5 eq.) was addedportionwise under vigorous stirring, and the mixture was stirredovernight. The mixture was diluted with CH₂Cl₂ (30 mL), and washed witha saturated NaHCO₃ solution. The organic layer was washed with brine,dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by column chromatography in (40-70%EA in PE) to give 82-14 as an oil. The residue was purified by TLC (50%EA in PE) to give pure 82-14 (350 mg 50%).

Compound 82-14 (350 mg, 0.86 mg) was treated with 7N NH₃ in MeOH (15mL). The mixture was stirred for 2-3 h and monitored by TLC. The mixturewas concentrated at low pressure, and the residue was purified by silicagel column chromatography (5% isopropanol in DCM) to give 82-15 (250 mg,96%) as a white solid. ¹H NMR (CD₃OD, 400 M Hz) δ=7.75 (d, J=7.9 Hz,1H), 6.60-6.35 (m, 1H), 5.72 (d, J=8.2 Hz, 1H), 5.37-5.25 (m, 1H),5.17-5.06 (m, 1H), 5.04-4.94 (m, 1H), 4.59-4.29 (m, 1H), 3.87-3.70 (m,2H).

To a stirred solution of 82-16 (3.79 g, 18 mmol) and 82-17 (3 g, 18mmol) in anhydrous DCM (60 mL) was added with a solution of TEA (4 g, 39mmol) in DCM (40 mL) dropwise at −78° C., and the mixture was stirredfor 2 h. The mixture was concentrated at low pressure, and the residuewas dissolved in methyl-butyl ether. The precipitate was removed byfiltration, and the filtrate was concentrated to give the crude product.The residue was purified by dry column chromatography (anhydrous DCM) togive pure 82-18 as a colorless oil (3 g, 54%).

Compound 82-15 (200 mg, 0.66 mmol) was coevaporated with toluene 3 timesto remove H₂O. Compound 82-15 was treated with MeCN (1.5 mL) and NMI(541 mg, 6.6 mmol). The mixture was stirred at R.T., and then 82-18 (403mg, 1.32 mmol) in MeCN (0.5 mL) was added. The residue was purified by asilica gel column (5% iPrOH in DCM) to give the crude product, which waspurified by HPLC (0.1% HCOOH in water and MeCN) to give compound 82 (33mg, 9%). ESI-LCMS: m/z 594 [M+Na]⁺.

Example 59 Compound 84

To a stirred solution of POCl₃ (2.0 g, 13 mmol) in anhydrous DCM (10 mL)was added 1-naphthol (1.88 g, 13 mmol) at −70° C. and TEA (1.31 g, 13mmol) in DCM (3 mL) dropwise at −70° C. The mixture was gradually warmedto R.T., and stirred for 1 h. A crude solution of 84-1 was obtained.

To a stirred solution of (S)-isobutyl 2-aminopropanoate hydrochloride(2.35 g, 13 mmol) in DCM (20 mL) was added TEA (2.63 g, 26 mmol) and acrude solution of 84-1 at −70° C. The mixture was gradually warmed toR.T., and stirred for 2 h. The reaction was monitored by LCMS andquenched with n-propylamine. The solvent was evaporated at low pressure,and the residue was purified by chromatography (PE:MTBE=5:1-1:1) to givepure 84-2 (1.8 g, 37%).

To a solution of 83-A (300 mg, 0.337 mmol) and NMI (276 mg, 3.37 mmol)in anhydrous CH₃CN (4 mL) was added 84-2 (249 mg, 0.674 mol, in DCM (5mL)) at 0° C. The mixture was stirred at R.T. for 10 h. The reaction wasmonitored by LCMS, and then quenched with H₂O. The mixture was extractedwith CH₂Cl₂ (3×20 mL). The organic phase was dried over anhydrous MgSO4,and concentrated at low pressure. The residue was purified bychromatography using PE:EA=5:1-2:1 as the eluent to give 84-3 (360 mg,87%).

Compound 84-3 (360 mg, 0.294 mmol) was dissolved in CH₃COOH (80%, 8 mL),and stirred at 40-50° C. for 2.5 h. The reaction was monitored by LCMSand then quenched with MeO. The mixture was concentrated at lowpressure, and the residue was purified by chromatography using PE:EA=1:1as the eluent to generate crude compound 84. The product purified byprep-HPLC (neutral system, NH₄HCO₃) to give compound 84 (70 mg, 75%) asa white solid. ESI-MS: m/z 679.2 [M+H]⁺.

Example 60 Compound 85

To a stirred solution of POCl₃ (2.0 g, 13 mmol) in anhydrous DCM (10 mL)was added phenol (1.22 g, 13 mmol) at −70° C. and TEA (1.31 g, 13 mmol)in DCM (3 mL) dropwise at −70° C. The mixture was gradually warmed toR.T., and stirred for 1 h. A crude solution of 85-1 was obtained.

Compound 85 was prepared using a similar procedure as for thepreparation of compound 84 using 85-2 (205 mg, 0.674 mol, in DCM (5 mL)obtained from (S)-isopropyl 2-aminopropanoate hydrochloride and 85-1)and 83-A (300 mg, 0.337 mmol). Compound 85 (50 mg, 74%) was obtained asa white solid. ESI-MS: m/z 615.2 [M+H]⁺.

Example 61 Compound 86

Compound 86 was prepared using a similar procedure as for thepreparation of compound 84 using 86-2 (214 mg, 0.674 mol, in DCM (5 mL)obtained from (S)-isobutyl 2-aminopropanoate hydrochloride and 86-1) and83-A (300 mg, 0.337 mmol). Compound 86 (70 mg, 87%) was obtained as awhite solid. ESI-MS: m/z 629.2 [M+H]⁺.

Example 62 Compound 87

Compound 87 was prepared using a similar procedure as for thepreparation of compound 84 using 87-2 (223 mg, 0.674 mol, DCM (5 mL)obtained from (S)-cyclopentyl 2-aminopropanoate hydrochloride and 87-1)and 83-A (300 mg, 0.337 mmol). Compound 87 (62 mg, 71%) was obtained asa white solid. ESI-MS: m/z 641.2 [M+H]⁺.

Example 63 Compound 88

Compound 88 was prepared using a similar procedure as for thepreparation of compound 84 using 88-2 (223 mg, 0.674 mol, DCM (5 mL),obtained from (S)-3-pentyl 2-aminopropanoate hydrochloride and 88-1) and83-A (300 mg, 0.337 mmol). Compound 88 (42 mg, 60%) was obtained as awhite solid. ESI-MS: m/z 643.2 [M+H]⁺.

Example 64 Compound 89

A stirred solution of phosphoryl trichloride (1.00 g, 6.58 mmol) and5-quinoline (955 mg, 6.58 mmol) in anhydrous DCM (50 mL) was treatedwith a solution of TEA (665 mg, 6.58 mmol) in DCM (10 mL) at −78° C. Themixture was gradually warmed to R.T., and stirred for 2 h. The solutionwas cooled to −78° C. and then treated with (5)-neopentyl2-aminopropanoate hydrochloride (1.28 g, 6.58 mmol). TEA (1.33 g, 13.16mmol) was added dropwise at −78° C. The mixture was gradually warmed toR.T., and stirred for 2 h. The mixture was concentrated at low pressure,and the residue was dissolved in methyl-butyl ether. The precipitate wasfiltered off, and the filtrate was concentrated at low pressure. Theresidue was purified by a silica gel column (pure AcOEt) to give 89-1 ascolorless oil (500 mg, 20%).

To a solution of 89-2 (300 mg, 0.337 mmol) and NMI (276.6 mg, 3.37 mmol)in anhydrous CH₃CN (0.9 mL) was added 89-1 (388 mg, 1.011 mmol) in CH₃CN(0.3 mL) dropwise at 0° C. The mixture was stirred at R.T. overnight.The reaction was quenched with water, and extracted with AcOEt. Theorganic phase was washed with brine, dried over anhydrous sodiumsulfate, and concentrated at low pressure. The residue was purified bysilica gel column (33% EA in PE) to give 89-3 as a yellow powder (300mg, 71.9%).

Compound 89-3 (300 mg, 0.243 mmol) was dissolved in 80% CH₃COOH (3 mL),and the mixture was stirred at 60° C. for 2.5 h. The mixture waspartitioned between AcOEt and water. The organic layer phase was washedby brine, dried over sodium sulfate and concentrated at low pressure.The residue was purified by silica gel column (50% EA in PE) to givecompound 89 as a yellow powder (81 mg, crude product). The crude product(81 mg) was purified by RP HPLC to give compound 89 as a white solid.(28.7 mg, 17.1%). ESI-LCMS: m/z 694.1 [M+H]⁺.

Example 65 Compound 90

Compound 90-1 was prepared using a similar procedure as for thepreparation of compound 89-1 using phosphoryl trichloride (2.00 g, 13.16mmol), 1-naphthol (1.882 g, 13.16 mmol) and (S)-neopentyl2-aminopropanoate hydrochloride (2.549 g, 13.16 mmol). Compound 90-1(600 mg, 12%) was obtained as a colorless oil.

A solution of 90-2 (230 mg 0.26 mmol) and NMI (212 mg 2.60 mmol) inanhydrous CH₃CN (1 mL) was treated with a solution of 90-1 (300 mg 0.78mmol) in anhydrous CH₃CN (0.5 mL) at R.T. The mixture was stirred atR.T. overnight. The reaction was quenched with water, and extracted withEA (3×20 mL). The organic layer was washed with brine, dried byanhydrous sodium sulfate, and concentrated at low pressure. The residuewas purified by a silica gel column (CH₃OH in CH₂Cl₂ from 1% to 5%) togive 90-3 (300 mg, 93%) as a white solid.

Compound 90-3 (300 mg, 0.24 mmol) was dissolved in CH₃COOH (80%, 5 mL).The mixture was stirred at 60° C. for 2.5 h. The mixture was dilutedwith EA (30 mL) and washed with brine. The organic phase was dried overanhydrous sodium sulfate, and concentrated at low pressure. The residuewas purified by a silica gel column (CH₃OH in CH₂Cl₂ from 1% to 5%) togive crude compound 90 (105 mg). The crude product was purified by HPLC(0.1% NH₄HCO₃ in water and CH₃CN) to give compound 90 (45 mg, 26%) as awhite solid. ESI-LCMS: m/z 693.2 [M+H]⁺.

Example 66 Compound 91

A stirred solution of 91-1 (2.00 g, 13.99 mmol) and 91-2 (2.00 g, 13.99mmol) in anhydrous DCM (8 mL) was treated with a solution of TEA (3.11g, 30.8 mmol) in DCM (20 mL) dropwise at −78° C. The mixture was stirredfor 2 h. at −78° C. and then gradually warmed to R.T. The organicsolvent was removed at low pressure, and the residue was dissolved inmethyl-butyl ether. The precipitate was filtered off, and the filtratewas concentrated at low pressure. The residue was purified on a silicagel column (dry DCM) to give 91-3 as colorless oil (1 g, 20.96%).

Compound 91-4 (260 mg, 0.29 mmol) was coevaporated with toluene 3 timesto remove H₂O. Dried 91-4 was treated with MeCN (0.8 mL) and NMI (240mg, 2.9 mmol) and then stirred for 10 mins. The mixture was treated witha solution of 91-3 (291 mg, 0.87 mmol) in MeCN (0.4 mL), and thenconcentrated at low pressure. The residue was purified on a silica gelcolumn (75% EA in PE)) to give 91-5 (300 mg, 86%) as a white solid.

Compound 91-5 (300 mg, 0.25 mmol) was treated with CH₃COOH (5 mL, 80%),and stirred at 50° C. for 3 h. The mixture was diluted with EA. Thesolution was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated at low pressure. The residue was purified by silica gelcolumn chromatography (67% EA in PE) to give crude compound 91, whichwas purified by HPLC. The product was dried by lyophilization to givecompound 91 (30 mg, 18.5%) as a white solid. ESI-LCMS: m/z 643 [M+H]⁺.

Example 67 Compound 77

To a solution of 1,1-dimethoxycyclopentane (19.3 g, 148.52 mmol) and77-1 (10.0 g, 37.13 mmol) in DCE (100 mL) was added TsOH.H₂O (0.7 g,3.71 mmol). The mixture was stirred at 50° C. for 12 h. The mixture wasneutralized with Et₃N, and concentrated at low pressure. The residue waspurified by silica gel column chromatography (1-10% MeOH in DCM) to give77-2 (8.7 g, 70.1%) as a white solid.

Compound 77-2 (20.0 g, 0.06 mol) was coevaporated with anhydrouspyridine 3 times to remove H₂O. To an ice-cold solution of 77-2 inanhydrous pyridine (100 mL) was added TsCl (22.8 g, 0.12 mol) at 0° C.,and the mixture was stirred overnight. The reaction was monitored byLCMS and TLC. The reaction was quenched with H₂O, and the mixtureextracted with EA (3×200 mL). The solution was dried over anhydrousNa₂SO₄ and evaporated at low pressure. The residue was purified bysilica gel column chromatography (DCM: MeOH=100:1 to 15:1) to give 77-3(20.0 g, 69.0%) as a white solid.

To a solution of 77-3 (20.0 g, 0.04 mol) in acetone (200 mL) was addedNaI (31.0 g, 0.2 mol), and the mixture was heated to reflux overnight.The reaction was monitored by LCMS. The reaction was quenched with asat. Na₂S₂O₃ solution. The solution was extracted with EA (3×200 mL).The organic layer was dried over anhydrous Na₂SO₄, and evaporated at lowpressure. The residue was purified by silica gel column chromatography(DCM: MeOH=100:1 to 15:1) to give 77-4 (15.0 g, 83.3%) as a white solid.

Compound 77-4 (13.4 g, 30.16 mmol) was treated with HCOOH (80%) in H₂Oat R.T. The solution was stirred at 60° C. for 2 h. The mixture wasconcentrated at low pressure. The residue was purified by columnchromatography (1%-10% MeOH in DCM) to give 77-5 (9.1 g, 80.0%) as awhite solid.

To a solution of 77-5 (5.0 g, 13.22 mmol) in anhydrous CH₃CN/THF (50 mL,1:1, v:v) was added DBU (6.0 g, 39.66 mmol) at R.T. The solution wasstirred at 50° C. for 1.5 h. The reaction was quenched with HCOOH at 0°C., and then concentrated at low pressure. The residue was purified bycolumn chromatography (50%-70% EA in PE) to give 77-6 (3.3 g, 48.1%) asa white solid.

To an ice-cold solution of 77-6 (2.1 g, 8.39 mmol) in anhydrous MeCN (21mL) was added NIS (2.4 g, 10.49 mmol) and TEA.3HF (1.0 g, 6.29 mmol)under N₂. The mixture was stirred at R.T. for 1 h. The reaction wasquenched with sat. NaHCO₃ and sat. Na₂SO₃ solution, and extracted withEA (3×100 mL). The organic phase was dried over anhydrous Na₂SO₄, andevaporated to dryness at low pressure. The residue was purified on asilica gel column (30%-50% EA in PE) to give 77-7 (1.3 g, 39.3%) as alight yellow solid.

To a stirred solution of 77-7 (3.2 g, 8.08 mmol) in anhydrous DCM (32mL) was added DMAP (2.5 g, 20.20 mmol) and Et₃N (2.5 g, 24.24 mmol) atR.T. The mixture was treated with BzCl (3.7 g, 26.66 mmol) at 0° C. andthen stirred at R.T. overnight. The reaction was quenched with water,and extracted with EA (3×60 mL). The organic phase was concentrated atlow pressure, and the residue was purified by column chromatography(20%-30% EA in PE) to give 77-8 (1.8 g, 31.6%) as a white solid.

Bu₄NOH (8.0 g, 13.74 mL, 55% in H₂O) was adjusted to pH=3-4 with TFA,and then cooled to R.T. To a solution of 77-8 (600 mg, 0.85 mmol) in DCM(10 mL) was added the Bu₄NOH solution and m-CPBA (917 mg, 4.25 mmol,80%) at R.T. The mixture was stirred at 25° C. for 48 h and then washedwith a sat. NaHCO₃ solution. The organic layer was directly passedthrough basic Al₂O₃ column, and the solvent was concentrated at lowpressure. The residue was purified by a silica gel column (20%-30% EA inPE) to give 77-9 (123 mg, 24.3%) as a white solid.

To a solution of 77-9 (300 mg, 0.50 mmol) in EA/hexane (20 mL, 1:1, v:v)was added Lindlar catalyst (200 mg) under N₂. The mixture was stirredunder H₂ (40 Psi) at 2° C. for 1.5 h. The suspension was filtered, andthe filtrate was treated with Lindlar catalyst (200 mg) under N₂, andstirred under H₂ (40 Psi) at 25° C. for 1.5 h. The mixture was filtered,and the filtrate was concentrated at low pressure to give crude 77-10(287 mg) as a white solid.

Compound 77-10 (287 mg, 0.48 mmol) was dissolved in NH₃/MeOH (30 mL, 7M). The mixture was stirred at R.T. for 24 h under N₂ and thenconcentrated at low pressure. The residue was purified by prep-HPLC(0.1% HCOOH in water and MeCN) to give 77-11 (50 mg, 34.7% over twosteps) as a white solid. ¹H-NMR (CD₃OD, 400 MHz)=7.86 (d, J=8.0 Hz 1H),6.26 (s, 1H), 5.62-5.86 (m, 1H), 5.49 (d, J=17.1 Hz, 1H), 5.30 (d,J=10.5 Hz, 1H), 4.41 (d, J=19.3 Hz, 1H), 3.71-3.86 (m, 1H).

Compound 77-11 (113 mg, 0.39 mmol) was co-evaporated with toluene 3times to remove H₂O. To a stirred solution of 77-11 (113 mg, 0.39 mmol)in a mixture of MeCN (0.5 mL) and NMI (320 mg, 3.90 mmol) was added asolution of 73-C (256 mg, 0.66 mmol) in MeCN (0.5 mL) at 0° C. Themixture was stirred at R.T. overnight and then concentrated at lowpressure. The residue was purified on a silica gel column (5% MeOH inDCM) to give crude compound 77, which purified by prep-HPLC (0.1% HCOOHin water and MeCN) to give compound 77 (45 mg, 20.1%) as a white solid.ESI-MS: m/z 538.2 [M−F]⁺ ESI-MS: m/z 580.2 [M+Na]⁺.

Example 68 Compound 78

To a solution of 77-9 (300 mg, 0.50 mmol) in MeOH (30 mL) was added wetPd/C (300 mg, 10%) under N₂. The mixture was stirred under H₂ (1 atm) at25° C. for 1.5 h. The suspension was filtered, and then concentrated atlow pressure to give crude 78-1 (307 mg) as a white solid.

Compound 78-1 (307 mg, 0.48 mmol) was dissolved in NH₃/MeOH (30 mL, 7M). The mixture was stirred at R.T. for 24 h under N₂ then concentratedat low pressure. The residue was purified by prep-HPLC (0.1% HCOOH inwater and MeCN) to give 78-2 (30 mg, 21% over two steps) as a whitesolid.

Compound 78-2 (91 mg, 0.31 mmol) was co-evaporated with toluene 3 timesto remove H₂O. To a stirred solution of 78-2 (91 mg, 0.31 mmol) in amixture of MeCN (0.5 mL) and NMI (254 mg, 3.90 mmol) was added asolution 73-C (203 mg, 0.66 mmol) in MeCN (0.5 mL) at 0° C. The mixturewas stirred at R.T. overnight and then concentrated at low pressure. Theresidue was purified on a silica gel column (5% MeOH in DCM) to thecrude compound 78, which purified by prep-HPLC (0.1% HCOOH in water andMeCN) to give compound 78 (30 mg, 17%) as a white solid. ESI-MS: m/z540.1 [M−F]⁺.

Example 69 Additional Compounds of Formula (I)

The foregoing syntheses are exemplary and can be used as a startingpoint to prepare a large number of additional compounds. Examples ofcompounds of Formula (I) that can be prepared in various ways, includingthose synthetic schemes shown and described herein, are provided below.Those skilled in the art will be able to recognize modifications of thedisclosed syntheses and to devise routes based on the disclosuresherein; all such modifications and alternate routes are within the scopeof the claims.

Example 70 HCV Replicon Assay Cells

Huh-7 cells containing the self-replicating, subgenomic HCV repliconwith a stable luciferase (LUC) reporter were cultured in Dulbecco'smodified Eagle's medium (DMEM) containing 2 mM L-glutamine andsupplemented with 10% heat-inactivated fetal bovine serum (FBS), 1%penicillin-streptomyocin, 1% nonessential amino acids, and 0.5 mg/mLG418.

Determination of Anti-HCV Activity

Determination of 50% inhibitory concentration (EC₅₀) of compounds in HCVreplicon cells were performed by the following procedure. On the firstday, 5,000 HCV replicon cells were plated per well in a 96-well plate.On the following day, test compounds were solubilized in 100% DMSO to100× the desired final testing concentration. Each compound was thenserially diluted (1:3) up to 9 different concentrations. Compounds in100% DMSO are reduced to 10% DMSO by diluting 1:10 in cell culturemedia. The compounds were diluted to 10% DMSO with cell culture media,which were used to dose the HCV replicon cells in 96-well format. Thefinal DMSO concentration was 1%. The HCV replicon cells were incubatedat 37° C. for 72 h. At 72 h, cells were processed when the cells arestill subconfluent. Compounds that reduce the LUC signal are determinedby Bright-Glo Luciferase Assay (Promega, Madison, Wis.). % Inhibitionwas determined for each compound concentration in relation to thecontrol cells (untreated HCV replicon) to calculate the EC₅₀.

Compounds of Formula (I) are active in the replicon assay. The antiviralactivity of exemplary compounds is shown in Table 2, where ‘A’ indicatesan EC₅₀<1 μM, ‘B’ indicates an EC₅₀≧1 μM and <10 μM, and ‘C’ indicatesan EC₅₀≧10 μM and <100 μM.

TABLE 2 Compound # EC₅₀ 2 A 3 A 5 A 11 A 13 B 14 A 16 A 17 A 18 A 19 A20 A 21 A 22 A 27 C 28 A 29 C 30 A 31 A 32 A 33 A 34 A 35 A 36 A 37 A 40B 41 B 42 A 43 A 49 A 51 B 52 A 53 A 54 A 55 A 56 A 57 A 58 A 59 C 60 C61 A 62 A 66 A 67 B 70 B 73 B 77 B 79 A 80 B 81 A 83 A 84 A 85 A 86 A 87A 88 A 89 A 90 A 91 A

Example 71 NS5B Inhibition Assay

The enzyme activity of NS5B570-Con1 (Delta-21) was measured as anincorporation of tritiated NMP into acid-insoluble RNA products. Thecomplementary IRES (cIRES) RNA sequence was used as a template,corresponding to 377 nucleotides from the 3′-end of HCV (−) strand RNAof the Con-1 strain, with a base content of 21% Ade, 23% Ura, 28% Cyt,and 28% Gua. The cIRES RNA was transcribed in vitro using a T7transcription kit (Ambion, Inc.) and purified using the Qiagen RNeasymaxi kit. HCV polymerase reactions contained 50 nM NS5B570-Con1, 50 nMcIRES RNA, about 0.5 μCi tritiated NTP, 1 μM of competing cold NTP, 20mM NaCl, 40 mM Tris-HCl (pH 8.0), 4 mM dithiothreitol, and 4 mM MgCl₂.Standard reactions were incubated for 2 h at 37° C., in the presence ofincreasing concentration of inhibitor. At the end of the reaction, RNAwas precipitated with 10% TCA, and acid-insoluble RNA products werefiltered on a size exclusion 96-well plate. After washing of the plate,scintillation liquid was added and radio labeled RNA products weredetected according to standard procedures with a Trilux Topcountscintillation counter. The compound concentration at which theenzyme-catalyzed rate was reduced by 50% (IC₅₀) was calculated byfitting the data to a non-linear regression (sigmoidal). The IC₅₀ valueswere derived from the mean of several independent experiments and areshown in Table 3. Compounds of Formula (I) showed activity in thisassay. A value of ‘A’ in the table below indicates an IC₅₀ of <1 μM, avalue of indicates an IC₅₀≧1 μM and <10 μM, and a value of ‘C’ indicatesan IC₅₀ value of ≧10 μM and <100 μM.

TABLE 3 Compound # IC₅₀  6 A  7a A  7b B  9 A 12 A 15 A 26 A 28 A 38 A44 A 46 A 50 A 63 A 64 A 69 A 76 A

Example 72 Assessment of Inhibition of Mitochondrial Function

Drug-associated dysfunction of mitochondria is believed to play a rolein the etiology of the various adverse symptoms that occur in patientstreated with antiviral nucleoside/nucleotides. For this reason,evaluation of compounds for their potential to inhibit mitochondrialfunction is useful. To assess the potential for nucleotide/nucleosideanalogs to interfere with normal mitochondrial functions and exhibitmitochondrial toxicity, the following were measured: (1) the ability ofnucleotides to be incorporated by human mitochondrial RNA polymerase invitro and (2) the cellular inhibition of the synthesis of themitochondrial DNA (mtDNA)-encoded protein, cytochrome c oxidase (COX-I),relative to the nuclear DNA (nDNA)-encoded mitochondrial proteinsuccinate dehydrogenase subunit A (SDH-A) in HepG2 cells. Controlcompounds and compounds of Formula (I) were studied in these assays.

Biochemical Assay

Arnold et al. “Sensitivity of Mitochondrial Transcription and Resistanceof RNA Polymerase II Dependent Nuclear Transcription to AntiviralRibonucleosides” PLoS Pathog (2012) 8(11): e1003030.doi:10.1371/journal.ppat.1003030, which is hereby incorporated byreference in its entirety.

Assessment of Incorporation of Nucleotides by Human Mitochondrial RNAPolymerase (HMRP)

DdRp Assay with Human Mitochondrial RNA Polymerase

The DdRp assay with human mitochondrial RNA polymerase was performedunder single turnover conditions where enzyme concentration is in excessof the primer/template. The ³³P-RNA/DNA primer/template was used at aconcentration of 100 nM, together with 320 nM enzyme. The standard 10-μLreactions were carried out at 30° C. for 1 minute with 100 μM of eachnucleotide 5′-triphosphate (NTP), 10 mM MgCl₂, 50 mM NaCl, 40 mM Tris,pH 7.5, and 1 mM DTT. The reaction was stopped by adding 20 μL offormamide loading dye containing 50 mM EDTA. RNA products were resolvedby electrophoresis on 22.5% TBE Urea polyacrylamide sequencing gels thatwere scanned using a TYPHOON PhosphorImager.

Results

As shown in both FIGS. 10 and 11, the appropriate natural nucleotideswere shown to be good substrates for incorporation by HMRP in eachtemplate. The template in FIG. 10 was designed to measure incorporationof UTP analogs. Primer/Template: (SEQ ID NO: 1) UUUUGCCGCGCC and (SEQ IDNO: 2) GGGAATGCTAGGCGCGGC. In the control water lanes, wherein nonucleotides were added, no incorporation was observed as indicated bythe lack of product band. As shown in FIG. 10, UTP and 3′-deoxy-UTP wereefficient substrates for incorporation as indicated by the prominentproduct band. The potential for misincorporation was assessed using thecontrol nucleotide CTP. As provided in FIG. 10, CTP was incorporated toa lesser extent relative to UTP. In contrast to UTP and 3′-deoxy-UTP,compounds of Formula (I) and 2′-Me-2′-F-UTP were not efficientsubstrates for incorporation by HMRP as demonstrated by the lack ofproduct band.

The template strand shown in FIG. 11 was designed to measure theincorporation of GTP analogs. Primer/Template: (SEQ ID NO: 3)UUUUGCCGCGCC and (SEQ ID NO: 4) GGGAATGCACGGCGCGGC. In the control waterlanes, no incorporation was observed as indicated by the lack of productband. GTP and 3′-deoxy-GTP were found to be efficient substrates forincorporation as demonstrated by the significant product bands. Thepotential for misincorporation was assessed using the control nucleotideATP. As shown by the lack of product band in FIG. 11, control ATP was apoor substrate for incorporation. Nucleotide analog 2′-Me-GTP (thenucleotide metabolite of monophosphate prodrug INX-0189/BMS-986094) wastested and found to be a good substrate for incorporation by HMRP asindicated by the product band. Nucleotide analog 2′-Me-2′-F-GTP(nucleotide metabolite of monophosphate prodrug GS-938) was tested andalso found to be incorporated by HMRP. In contrast, compounds of Formula(I) were not efficient substrates for incorporation into the templatestrand by HMRP as indicated by the lack of product bands in FIG. 11.

Assessment of Inhibition of Mitochondrial Protein Synthesis—Cell BasedAssay Assay Principle

MitoBiogenesis™ In Cell ELISA kits (Cat. #MS643) were obtained fromMitosciences, OR, USA. The MitoBiogenesis™ In Cell ELISA kit is aduplexing 96 well assay that ratios both an mtDNA and an nDNA encodedmitochondrial protein. Cells were seeded in 96 microplates and afterexposure to compounds for several cell doublings, the levels of the twomitochondrial proteins were measured simultaneously in each well. Thetwo proteins assayed were each subunits of different oxidativephosphorylation enzyme complexes, one protein being subunit I of ComplexIV (cytochrome c oxidase; COX I) that is mtDNA encoded and the otherbeing the 70 kDa subunit of Complex II (succinate dehydrogenase subunitA; SDH A) that is nDNA encoded. Complex IV includes several proteinsthat are encoded by the mtDNA while the proteins of Complex II areentirely encoded by nDNA. To control for the density of cells present atthe end of the culture period, the number of cells were assessed bystaining with Janus Green and the levels of COX I/SDH A normalized tothe final cell density.

96 Well Plate Assay Format for HepG2 Cells

On the first day, 1000 HepG2 cells per well were plated in a 96 wellplate. On the following day, compounds to be tested were solubilized in100% DMSO to 100× the desired final testing concentration. Each compoundwas serially diluted (1:3) up to 9 distinct concentrations. Compounds in100% DMSO were reduced to 10% (v/v) DMSO by diluting 1:10 in cellculture media. A 10 μL aliquot of the compounds diluted to 10% (v/v)DMSO with cell culture media was used to dose the cells in duplicate.The final DMSO concentration was 1% (v/v). Untreated cells and wellscontaining no cells were included on the plate to serve as controls.Cells were then incubated with compounds and observed for 8 days at 37°C. and 5% CO₂. Plates were processed as described below in the assayprocedure.

Batch Assay Format for HepG2 Cells

An alternate cell culture procedure was employed to test the potentialto mediate mitochondrial toxicity at higher concentrations thanachievable in the 96 well plate format. HepG2 cells were grown either inmedia/DMSO alone or in a series of compound concentrations in 15 cm²dishes or 6 well plates at an initial cell seeding density of 5×10⁶ and5×10⁴ cells/mL, respectively. Cells were then incubated and observed for8 days at 37° C. and 5% CO₂. After 8 days, the cells were harvested bytrypsinization, counted, and seeded in 96 well plates at a density of25,000 cells/well in 16 replicate wells. Cells were allowed to adhereovernight and then the plates were processed as described below in theassay procedure.

Assay Procedure

The assay was performed according to the manufacturer's instructions.Briefly, after the end of the culture period the cell culture media wasgently aspirated from the wells of the plate and replaced with 100 μL of4% (v/v) paraformaldehyde solution in phosphate buffered saline (PBS,Electron Microscopy Sciences Cat. #15713). After a 20 mins incubation atR.T., the solution was removed and the wells washed 3× with 300 μL ofPBS. After the final wash, the PBS was removed and the wells overlayedwith 100 μL PBS. The plates were then sealed and stored at 4° C. untilused. To perform the assay, the PBS overlay was removed by blotting on apaper towel and 100 μL of 0.5% (v/v) acetic acid added to each well toblock endogenous alkaline phosphatase activity. After a 5 minsincubation at R.T., the acetic acid solution was removed and the cellswashed once with 200 μL PBS. Then, 100 μL of permeabilization buffer(0.1% (v/v) Triton×100) was added to each well. After 30 mins incubationat R.T., the permeabilization buffer was removed and each well wasblocked with 200 μL of 2× blocking solution for 2 h at R.T. The 2×blocking solution was then removed and 100 μL of primary antibodysolution containing anti COX I and anti SDH A antibodies in 1× blockingsolution was added to each well. Plates were then sealed and incubatedovernight at 4° C. The primary antibody/blocking solution was removedand the plate washed 3× with 250 μL 0.05% (v/v) Tween 20 in PBS. Then,100 μL of secondary antibody solution containing alkaline phosphatase(AP) labeled anti SDH A antibody and horseradish peroxidase (HRP)labeled anti COX I antibody was added and incubated for 1 h at R.T. Theplate was then washed 4× with 250 μL 0.05% (v/v) Tween 20 in PBS. Afterblotting the plate dry 100 μL of AP detection reagent was added to eachwell, and the plate incubated in the dark for 30 mins at R.T. Theoptical density of each well was then measured at 405 nm. The APdetection reagent was then removed and replaced with 100 μL of HRPdetection reagent, and the plate incubated in the dark for a further 30mins at R.T. The optical density of each well was then measured at 600nm. The HRP detection reagent was then removed and each well was thenstained with 50 μL of 1× Janus Green Stain for 5 mins at R.T. Afterremoval of the dye, the plates were washed 5× in ultrapure water toremove any remaining dye. The Janus Green stain was then solubilized bythe addition of 100 μL of 0.5 M HCl and incubated for 10 mins. Theoptical density of each well was then measured at 595 nm.

Data Analysis

The average of all replicate background measurements from eachexperimental condition was calculated and subtracted from theexperimental values of the same condition. The SDH A and COX I signalswere then plotted as a ratio (COX I/SDH A) and normalized to the JanusGreen staining intensity to correct for differences in cell density.

Results

Control compound d4T was tested and found not to inhibit mitochondrialprotein synthesis at concentrations up to 100 μM as shown in FIGS.12A-D. Control compound ddC was tested and found to strongly inhibitmitochondrial protein synthesis. See FIGS. 12A-D. As demonstrated inFIG. 12A, nucleoside monophosphate prodrug INX-08189/BMS-986094 (whichdelivers 2′-Me-GTP) was tested in the assay and found to stronglyinhibit mitochondrial protein synthesis. In contrast, compounds ofFormula (I) were tested and found to not inhibit mitochondrial proteinsynthesis at concentrations up to 100 μM as shown in FIGS. 12B-D.

Example 73 Combination of Compounds Combination Testing

Two or more test compounds were tested in combination with each otherusing an HCV genotype 1b HCV replicon harbored in Huh7 cells with astable luciferase (LUC) reporter. Cells were cultured under standardconditions in Dulbecco's modified Eagle's medium (DMEM; Mediatech Inc,Herndon, Va.) containing 10% heat-inactivated fetal bovine serum (FBS;Mediatech Inc, Herndon, Va.) 2 mM L-glutamine, and nonessential aminoacids (JRH Biosciences). HCV replicon cells were plated in a 96-wellplate at a density of 10⁴ cells per well in DMEM with 10% FBS. On thefollowing day, the culture medium was replaced with DMEM containingeither no compound as a control, the test compounds serially diluted inthe presence of 2% FBS and 0.5% DMSO, or a combination of compound 18with one or more test compounds serially diluted in the presence of 2%FBS and 0.5% DMSO. The cells were incubated with no compound as acontrol, with the test compounds, or the combination of compounds for 72h. The direct effects of the combination of the test compounds wereexamined using a luciferase (LUC) based reporter as determined by theBright-Glo Luciferase Assay (Promega, Madison, Wis.). Dose-responsecurves were determined for individual compounds and fixed ratiocombinations of two or more test compounds.

The method utilized for evaluating combination effects used a programcalled MacSynergy II. MacSynergy II software was kindly provided by Dr.M. Prichard (University of Michigan). The Prichard Model allows for athree-dimensional examination of drug interactions and a calculation ofthe synergy volume (units: μM²%) generated from running the repliconassay using a checkerboard combination of two or more inhibitors. Thevolumes of synergy (positive volumes) or antagonism (negative volumes)represent the relative quantity of synergism or antagonism per change inthe concentrations of the two drugs. Synergy and antagonism volumes aredefined based on the Bliss independence model. In this model, synergyvolumes of less than −25 indicate antagonistic interactions, volumes inthe −25-25 range indicate additive behavior, volumes in the 25-100 rangeindicate synergistic behavior and volumes >100 indicate strongsynergistic behavior. Determination of in vitro additive, synergisticand strongly synergistic behavior for combinations of compounds can beof utility in predicting therapeutic benefits for administering thecombinations of compounds in vivo to infected patients.

The synergy volume results for the combinations are provided in Table 4.

TABLE 4 Combination Synergy Volume Compound (μM² %) DeterminationANA-598 29.46 Synergistic (3002) HCV-796 81.72 Synergistic (3004)Ribavirin 6.77 Additive (5012) Filibuvir 23.51 Additive (3007) VX-22232.35 Synergistic (3003) BMS-790052 38.01 Synergistic (4001) VX-95032.28 Synergistic (1001) TMC-435 97.17 Synergistic (1013)

Although the foregoing has been described in some detail by way ofillustrations and examples for purposes of clarity and understanding, itwill be understood by those of skill in the art that numerous andvarious modifications can be made without departing from the spirit ofthe present disclosure. Therefore, it should be clearly understood thatthe forms disclosed herein are illustrative only and are not intended tolimit the scope of the present disclosure, but rather to also cover allmodification and alternatives coming with the true scope and spirit ofthe invention.

1. (canceled)
 2. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt of the foregoing.
 3. A compoundselected from the group consisting of:

or a pharmaceutically acceptable salt of the foregoing.
 4. A compoundselected from the group consisting of:

or a pharmaceutically acceptable salt of the foregoing.